Modified 2&#39; and 3&#39;-nucleoside prodrugs for treating flaviviridae infections

ABSTRACT

2′ and/or 3′ prodrugs of 1′, 2′, 3′ or 4′-branchednucleosides, and their pharmaceutically acceptable salts and derivatives are described. These prodrugs are useful in the prevention and treatment of Flaviviridae infections, including HCV infection, and other related conditions. Compounds and compositions of the prodrugs of the present invention are described. Methods and uses are also provided that include the administration of an effective amount of the prodrugs of the present invention, or their pharmaceutically acceptable salts or derivatives. These drugs may optionally be administered in combination or alteration with further anti-viral agents to prevent or treat Flaviviridae infections and other related conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisionalapplication No. 60/392,350, filed Jun. 28, 2002; U.S. ProvisionalApplication No. 60/466,194, filed Apr. 28, 2003; and U.S. ProvisionalApplication No. 60/470,949, filed May 14, 2003, the disclosures of eachof which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention is in the area of pharmaceutical chemistry, and is inparticular, a 2′ and/or 3′ prodrug of 6-modified, 1′, 2′, 3′ or4′-branched pyrimidine nucleoside or 8-modified, 1′, 2′, 3′ or4′-branched purine nucleoside for the treatment of a Flaviviridaeinfection, such as a hepatitis C virus infection.

BACKGROUND OF THE INVENTION Flaviviridae Viruses

The Flaviviridae family of viruses comprises at least three distinctgenera: pestiviruses, which cause disease in cattle and pigs;flaviviruses, which are the primary cause of diseases such as denguefever and yellow fever; and hepaciviruses, whose sole member is HCV. Theflavivirus genus includes more than 68 members separated into groups onthe basis of serological relatedness (Calisher et al., J. Gen. Virol,1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitisand hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe,D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia,Pa., 1996, Chapter 31, 931-959). Flaviviruses of global concern that areassociated with human disease include the dengue hemorrhagic feverviruses (DHF), yellow fever virus, shock syndrome and Japaneseencephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6,251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., NewEng. J. Med., 1988, 319, 641-643).

The pestivirus genus includes bovine viral diarrhea virus (BVDV),classical swine fever virus (CSFV, also called hog cholera virus) andborder disease virus (BDV) of sheep

(Moennig, V. et al. Adv. Vir. Res. 1992, 41, 53-98). Pestivirusinfections of domesticated livestock (cattle, pigs and sheep) causesignificant economic losses worldwide. BVDV causes mucosal disease incattle and is of significant economic importance to the livestockindustry (Meyers, G. and Thiel, H.-J., Advances in Virus Research, 1996,47, 53-118; Mocnnig V., et al, Adv. Vir. Res. 1992, 41, 53-98). Humanpestiviruses have not been as extensively characterized as the animalpestiviruses. However, serological surveys indicate considerablepestivirus exposure in humans.

Pestiviruses and hepaciviruses are closely related virus groups withinthe Flaviviridae family. Other closely related viruses in this familyinclude the GB virus A, GB virus A-like agents, GB virus-B and GBvirus-C (also called hepatitis G virus, HGV). The hepacivirus group(hepatitis C virus; HCV) consists of a number of closely related butgenotypically distinguishable viruses that infect humans. There areapproximately 6 HCV genotypes and more than 50 subtypes. Due to thesimilarities between pestiviruses and hepaciviruses, combined with thepoor ability of hepaciviruses to grow efficiently in cell culture,bovine viral diarrhea virus (BVDV) is often used as a surrogate to studythe HCV virus.

The genetic organization of pestiviruses and hepaciviruses is verysimilar. These positive stranded RNA viruses possess a single large openreading frame (ORF) encoding all the viral proteins necessary for virusreplication. These proteins are expressed as a polyprotein that is co-and post-translationally processed by both cellular and virus-encodedproteinases to yield the mature viral proteins. The viral proteinsresponsible for the replication of the viral genome RNA are locatedwithin approximately the carboxy-terminal. Two-thirds of the ORF aretermed nonstructural (NS) proteins. The genetic organization andpolyprotein processing of the nonstructural protein portion of the ORFfor pestiviruses and hepaciviruses is very similar. For both thepestiviruses and hepaciviruses, the mature nonstructural (NS) proteins,in sequential order from the amino-terminus of the nonstructural proteincoding region to the carboxy-terminus of the ORF, consist of p7, NS2,NS3, NS4A, NS4B, NS5A, and NS5B.

The NS proteins of pestiviruses and hepaciviruses share sequence domainsthat are characteristic of specific protein functions. For example, theNS3 proteins of viruses in both groups possess amino acid sequencemotifs characteristic of serine proteinases and of helicases (Gorbalenyaet al. (1988) Nature 333:22; Bazan and Fletterick (1989) Virology171:637-639; Gorbalenya et al. (1989) Nucleic Acid Res. 17.3889-3897).Similarly, the NS5B proteins of pestiviruses and hepaciviruses have themotifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. andDolja, V. V. (1993) Crit. Rev. Biochem. Molec. Biol. 28:375-430).

The actual roles and functions of the NS proteins of pestiviruses andhepaciviruses in the lifecycle of the viruses are directly analogous. Inboth cases, the NS3 serine proteinase is responsible for all proteolyticprocessing of polyprotein precursors downstream of its position in theORF (Wiskerchen and Collett (1991) Virology 184:341-350; Bartenschlageret al. (1993) J. Virol. 67:3835-3844; Eckart et al. (1993) Biochem.Biophys. Res. Comm. 192:399-406; Grakoui et al. (1993) J. Virol.67:2832-2843; Grakoui et al. (1993) Proc. Natl. Acad. Sci. USA90:10583-10587; Hijikata et al. (1993) J. Virol. 67:4665-4675; Tome etal. (1993) J. Virol. 67:4017-4026). The NS4A protein, in both cases,acts as a cofactor with the NS3 serine protease (Bartenschlager et al.(1994) J. Virol. 68:5045-5055; Failla et al. (1994) J. Virol. 68:3753-3760; Lin et al. (1994) 68:8147-8157; Xu et al. (1997) J. Virol.71:5312-5322). The NS3 protein of both viruses also functions as ahelicase (Kim et al. (1995) Biochem. Biophys. Res. Comm. 215: 160-166;Jin and Peterson (1995) Arch. Biochem. Biophys., 323:47-53; Warrener andCollett (1995) J. Virol. 69:1720-1726). Finally, the NS5B proteins ofpestiviruses and hepaciviruses have the predicted RNA-directed RNApolymerases activity (Behrens et al. (1996) EMBO J. 15:12-22; Lchmannet. al. (1997) J. Virol. 71:8416-8428; Yuan et al. (1997) Biochem.Biophys. Res. Comm. 232:231-235; Hagedorn, PCT WO 97/12033; Zhong et al.(1998) J. Virol. 72.9365-9369).

Hepatitis C Virus

The hepatitis C virus (HCV) is the leading cause of chronic liverdisease worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000). HCVcauses a slow growing viral infection and is the major cause ofcirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon,B. R., Scientific American, Oct.: 80-85, (1999); Boyer, N. et al. J.Hepatol. 32:98-112, 2000). An estimated 170 million persons are infectedwith HCV worldwide. (Boyer, N. et al. J. Hepatol. 32:98-112, 2000).Cirrhosis caused by chronic hepatitis C infection accounts for8,000-12,000 deaths per year in the United States, and HCV infection isthe leading indication for liver transplantation.

HCV is known to cause at least 80% of posttransfusion hepatitis and asubstantial proportion of sporadic acute hepatitis. Preliminary evidencealso implicates HCV in many cases of “idiopathic” chronic hepatitis,“cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelatedto other hepatitis viruses, such as Hepatitis B Virus (HBV). A smallproportion of healthy persons appear to be chronic HCV carriers, varyingwith geography and other epidemiological factors. The numbers maysubstantially exceed those for HBV, though information is stillpreliminary; how many of these persons have subclinical chronic liverdisease is unclear. (The Merck Manual, ch. 69, p. 901, 16th ed.,(1992)).

HCV is an enveloped virus containing a positive-sense single-strandedRNA genome of approximately 9.4 kb. The viral genome consists of a 5′untranslated region (UTR), a long open reading frame encoding apolyprotein precursor of approximately 3011 amino acids, and a short 3′UTR. The 5′ UTR is the most highly conserved part of the HCV genome andis important for the initiation and control of polyprotein translation.Translation of the HCV genome is initiated by a cap-independentmechanism known as internal ribosome entry. This mechanism involves thebinding of ribosomes to an RNA sequence known as the internal ribosomeentry site (IRES). An RNA pseudoknot structure has recently beendetermined to be an essential structural element of the HCV IRES. Viralstructural proteins include a nucleocapsid core protein (C) and twoenvelope glycoproteins, E1 and E2. HCV also encodes two proteinases, azinc-dependent metalloproteinase encoded by the NS2-NS3 region and aserine proteinase encoded in the NS3 region. These proteinases arerequired for cleavage of specific regions of the precursor polyproteininto mature peptides. The carboxyl half of nonstructural protein 5,NS5B, contains the RNA-dependent RNA polymerase. The function of theremaining nonstructural proteins, NS4A and NS4B, and that of NS5A (theamino-terminal half of nonstructural protein 5) remain unknown.

A significant focus of current antiviral research is directed to thedevelopment of improved methods of treatment of chronic HCV infectionsin humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American,Oct.: 80-85, (1999)).

Treatment of HCV Infection with Interferon

Interferons (IFNs) have been commercially available for the treatment ofchronic hepatitis for nearly a decade. IFNs are glycoproteins producedby immune cells in response to viral infection. IFNs inhibit replicationof a number of viruses, including HCV, and when used as the soletreatment for hepatitis C infection, IFN can in certain cases suppressserum HCV-RNA to undetectable levels. Additionally, IFN can normalizeserum amino transferase levels. Unfortunately, the effect of IFN istemporary and a sustained response occurs in only 8%-9% of patientschronically infected with HCV (Gary L. Davis. Gastroenterology118:S104-S114, 2000). Most patients, however, have difficulty toleratinginterferon treatment, which causes severe flu-like symptoms, weightloss, and lack of energy and stamina.

A number of patents disclose Flaviviridae, including HCV, treatments,using interferon-based therapies. For example, U.S. Pat. No. 5,980,884to Blatt et al. discloses methods for retreatment of patients afflictedwith HCV using consensus interferon. U.S. Pat. No. 5,942,223 to Bazer etal. discloses an anti-HCV therapy using ovine or bovine interferon-tau.U.S. Pat. No. 5,928,636 to Alber et al. discloses the combinationtherapy of interleukin-12 and interferon alpha for the treatment ofinfectious diseases including HCV. U.S. Pat. No. 5,849,696 to Chretienet al. discloses the use of thymosins, alone or in combination withinterferon, for treating HCV. U.S. Pat. No. 5,830,455 to Valtuena et al.discloses a combination HCV therapy employing interferon and a freeradical scavenger. U.S. Pat. No. 5,738,845 to Imakawa discloses the useof human interferon tau proteins for treating HCV. Otherinterferon-based treatments for HCV are disclosed in U.S. Pat. No.5,676,942 to Testa et al., U.S. Pat. No. 5,372,808 to Blatt et al., andU.S. Pat. No. 5,849,696. A number of patents also disclose pegylatedforms of interferon, such as, U.S. Pat. Nos. 5,747,646, 5,792,834 and5,834,594 to Hoffmann-La Roche Inc; PCT Publication No. WO 99/32139 andWO 99/32140 to Enzon; WO 95/13090 and U.S. Pat. Nos. 5,738,846 and5,711,944 to Schering; and U.S. Pat. No. 5,908,621 to Glue et al.

Interferon alpha-2a and interferon alpha-2b are currently approved asmonotherapy for the treatment of HCV. ROFERON®-A (Roche) is therecombinant form of interferon alpha-2a. PEGASYS® (Roche) is thepegylated (i.e. polyethylene glycol modified) form of interferonalpha-2a. INTRON®A (Schering Corporation) is the recombinant form ofInterferon alpha-2b, and PEG-INTRON® (Schering Corporation) is thepegylated form of interferon alpha-2b.

Other forms of interferon alpha, as well as interferon beta, gamma, tauand omega are currently in clinical development for the treatment ofHCV. For example, INFERGEN (interferon alphacon-1) by InterMune,OMNIFERON (natural interferon) by Viragen, ALBUFERON by Human GenomeSciences, REBIF (interferon beta-1a) by Ares-Serono, Omega Interferon byBioMedicine, Oral Interferon Alpha by Amarillo Biosciences, andinterferon gamma, interferon tau, and interferon gamma-1b by InterMuneare in development.

Ribivarin

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is asynthetic, non-interferon-inducing, broad spectrum antiviral nucleosideanalog sold under the trade name, Virazole (The Merck Index, 11thedition, Editor: Budavari, S., Merck & Co., Inc., Rahway, N.J., p 1304,1989). U.S. Pat. No. 3,798,209 and RE29,835 disclose and claimribavirin. Ribavirin is structurally similar to guanosine, and has invitro activity against several DNA and RNA viruses includingFlaviviridae (Gary L. Davis. Gastroenterology 118:S104-S114, 2000).

Ribavirin reduces serum amino transferase levels to normal in 40% ofpatients, but it does not lower serum levels of HCV-RNA (Gary L. Davis.Gastroenterology 118:S104-S114, 2000). Thus, ribavirin alone is noteffective in reducing viral RNA levels. Additionally, ribavirin hassignificant toxicity and is known to induce anemia.

Ribavirin is not approved fro monotherapy against HCV. It has beenapproved in combination with interferon alpha-2a or interferon alpha-2bfor the treatment of HCV.

Combination of Interferon and Ribavirin

The current standard of care for chronic hepatitis C is combinationtherapy with an alpha interferon and ribavirin. The combination ofinterferon and ribavirin for the treatment of HCV infection has beenreported to be effective in the treatment of interferon naïve patients(Battaglia, A. M. et al., Ann. Pharmacother. 34:487-494, 2000), as wellas for treatment of patients when histological disease is present(Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998). Studieshave show that more patients with hepatitis C respond to pegylatedinterferon-alpha/ribavirin combination therapy than to combinationtherapy with unpegylated interferon alpha. However, as with monotherapy,significant side effects develop during combination therapy, includinghemolysis, flu-like symptoms, anemia, and fatigue. (Gary L. Davis.Gastroenterology 118:S104-S114, 2000).

Combination therapy with PEG-INTRON® (peginterferon alpha-2b) andREBETOL® (Ribavirin, USP) Capsules is available from ScheringCorporation. REBETOL® (Schering Corporation) has also been approved incombination with INTRON® A (Interferon alpha-2b, recombinant, ScheringCorporation). Roche's PEGASYS® (pegylated interferon alpha-2a) andCOPEGUS® (ribavirin) are also approved for the treatment of HCV.

PCT Publication Nos. WO 99/59621, WO 00/37110, WO 01/81359, WO 02/32414and WO 03/024461 by Schering Corporation disclose the use of pegylatedinterferon alpha and ribavirin combination therapy for the treatment ofHCV. PCT Publication Nos. WO 99/15194, WO 99/64016, and WO 00/24355 byHoffmann-La Roche Inc also disclose the use of pegylated interferonalpha and ribavirin combination therapy for the treatment of HCV.

Additional Methods to Treat Flaviviridae Infections

The development of new antiviral agents for flaviviridae infections,especially hepatitis C, is currently underway. Specific inhibitors ofHCV-derived enzymes such as protease, helicase, and polymeraseinhibitors are being developed. Drugs that inhibit other steps in HCVreplication are also in development, for example, drugs that blockproduction of HCV antigens from the RNA (IRES inhibitors), drugs thatprevent the normal processing of HCV proteins (inhibitors ofglycosylation), drugs that block entry of HCV into cells (by blockingits receptor) and nonspecific cytoprotective agents that block cellinjury caused by the virus infection. Further, molecular approaches arealso being developed to treat hepatitis C, for example, ribozymes, whichare enzymes that break down specific viral RNA molecules, and antisenseoligonucleotides, which are small complementary segments of DNA thatbind to viral RNA and inhibit viral replication, are underinvestigation. A number of HCV treatments are reviewed by Bymock et al.in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000) and DeFrancesco et al. in Antiviral Research, 58: 1-16 (2003).

Examples of classes of drugs that are being developed to treatFlaviviridae infections include:

-   -   (1) Protease inhibitors

Substrate-based NS3 protease inhibitors (Attwood et at, Antiviralpeptide derivatives, PCT WO 98/22496, 1998; Attwood et al., AntiviralChemistry and Chemotherapy 1999, 10, 259-273; Attwood et al.,Preparation and use of amino acid derivatives as anti-viral agents,German Patent Pub. DE 19914474; Tung et al. Inhibitors of serineproteases, particularly hepatitis C virus NS3 protease, PCT WO98/17679), including alphaketoamides and hydrazinoureas, and inhibitorsthat terminate in an electrophile such as a boronic acid or phosphonate(Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO99/07734) are being investigated.

Non-substrate-based NS3 protease inhibitors such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,Biochemical and Biophysical Research Communications, 1997, 238, 643-647;Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186),including RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup are also being investigated.

Sch 68631, a phenanthrenequinone, is an HCV protease inhibitor (Chu M.et al., Tetrahedron Letters 37:7229-7232, 1996). In another example bythe same authors, Sch 351633, isolated from the fungus Penicilliumgriseofulvum, was identified as a protease inhibitor (Chu M. et al.,Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Nanomolarpotency against the HCV NS3 protease enzyme has been achieved by thedesign of selective inhibitors based on the macromolecule eglin c. Eglinc, isolated from leech, is a potent inhibitor of several serineproteases such as S. griseus proteases A and B, α-chymotrypsin, chymaseand subtilisin. Qasim M. A. et al., Biochemistry 36:1598-1607, 1997.

Several U.S. patents disclose protease inhibitors for the treatment ofHCV. For example, U.S. Pat. No. 6,004,933 to Spruce et al. discloses aclass of cysteine protease inhibitors for inhibiting HCV endopeptidase2. U.S. Pat. No. 5,990,276 to Zhang et al. discloses syntheticinhibitors of hepatitis C virus NS3 protease. The inhibitor is asubsequence of a substrate of the NS3 protease or a substrate of theNS4A cofactor. The use of restriction enzymes to treat HCV is disclosedin U.S. Pat. No. 5,538,865 to Reyes et al. Peptides as NS3 serineprotease inhibitors of HCV are disclosed in WO 02/008251 to CorvasInternational, Inc, and WO 02/08187 and WO 02/008256 to ScheringCorporation. HCV inhibitor tripeptides are disclosed in U.S. Pat. Nos.6,534,523, 6,410,531, and 6,420,380 to Boehringer Ingelheim and WO02/060926 to Bristol Myers Squibb. Diaryl peptides as NS3 serineprotease inhibitors of HCV are disclosed in WO 02/48172 to ScheringCorporation. Imidazoleidinones as NS3 serine protease inhibitors of HCVare disclosed in WO 02/08198 to Schering Corporation and WO 02/48157 toBristol Myers Squibb. WO 98/17679 to Vertex Pharmaceuticals and WO02/48116 to Bristol Myers Squibb also disclose HCV protease inhibitors.

-   -   (2) Thiazolidine derivatives which show relevant inhibition in a        reverse-phase HPLC assay with an NS3/4A fusion protein and        NS5A/5B substrate (Sudo K. et al., Antiviral Research, 1996, 32,        9-18), especially compound RD-1-6250, possessing a fused        cinnamoyl moiety substituted with a long alkyl chain, RD4 6205        and RD4 6193;    -   (3) Thiazolidines and benzanilides identified in Kakiuchi N. et        al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical        Biochemistry, 1997, 247, 242-246;    -   (4) A phenan-threnequinone possessing activity against protease        in a SDS-PAGE and autoradiography assay isolated from the        fermentation culture broth of Streptomyces sp., Sch 68631        (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and        Sch 351633, isolated from the fungus Penicillium griseofulvum,        which demonstrates activity in a scintillation proximity assay        (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9,        1949-1952);    -   (5) Helicase inhibitors (for example Diana G. D. et al.,        Compounds, compositions and methods for treatment of hepatitis        C, U.S. Pat. No. 5,633,358; Diana G. D. et al., Piperidine        derivatives, pharmaceutical compositions thereof and their use        in the treatment of hepatitis C, PCT WO 97/36554);    -   (6) Nucleotide polymerase inhibitors and gliotoxin (Ferrari R.        et al. Journal of Virology, 1999, 73, 1649-1654), and the        natural product cerulenin (Lohmann V. et al., Virology, 1998,        249, 108-118);    -   (7) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)        complementary to sequence stretches in the 5′ non-coding region        (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22,        707-717), or nucleotides 326-348 comprising the 3′ end of the        NCR and nucleotides 371-388 located in the core coding region of        the HCV RNA (Alt M. et al., Archives of Virology, 1997, 142,        589-599; Galderisi U. et al., Journal of Cellular Physiology,        1999, 181, 251-257);    -   (8) Inhibitors of IRES-dependent translation (Ikeda N et al.,        Agent for the prevention and treatment of hepatitis C, Japanese        Patent Pub. JP-08268890; Kai Y. et al. Prevention and treatment        of viral diseases, Japanese Patent Pub. JP-10101591);    -   (9) Ribozymes, such as nuclease-resistant ribozymes        (Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995) and        those disclosed in U.S. Pat. No. 6,043,077 to Barber et al., and        U.S. Pat. Nos. 5,869,253 and 5,610,054 to Draper et al.; and    -   (10) Nucleoside analogs have also been developed for the        treatment of Flaviviridae infections.

Idenix Pharmaceuticals discloses the use of branched nucleosides in thetreatment of flaviviruses (including HCV) and pestiviruses inInternational Publication Nos. WO 01/90121 and WO 01/92282.Specifically, a method for the treatment of hepatitis C infection (andflaviviruses and pestiviruses) in humans and other host animals isdisclosed in the Idenix publications that includes administering aneffective amount of a biologically active 1′, 2′, 3′ or 4′-branched β-Dor β-L nucleosides or a pharmaceutically acceptable salt or derivativethereof, administered either alone or in combination with anotherantiviral agent, optionally in a pharmaceutically acceptable carrier.

Other patent applications disclosing the use of certain nucleosideanalogs to treat hepatitis C virus include: PCT/CA00/01316 (WO 01/32153;filed Nov. 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed Feb. 19,2001) filed by BioChem Pharma, Inc. (now Shire Biochem, Inc.);PCT/US02/01531 (WO 02/057425; filed Jan. 18, 2002) and PCT/US02/03086(WO 02/057287; filed Jan. 18, 2002) filed by Merck & Co., Inc.,PCT/EP01/09633 (WO 02/18404; published Aug. 21, 2001) filed by Roche,and PCT Publication Nos. WO 01/79246 (filed Apr. 13, 2001), WO 02/32920(filed Oct. 18, 2001) and WO 02/48165 by Pharmasset, Ltd.

PCT Publication No. WO 99/43691 to Emory University, entitled“2′-Fluoronucleosides” discloses the use of certain 2′-fluoronucleosidesto treat HCV.

Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^(th)International Conference on Antiviral Research (Apr. 27, 2003, Savannah,Ga.)) described the structure activity relationship of 2′-modifiednucleosides for inhibition of HCV.

Bhat et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 2003 (OralSession V, Hepatitis C Virus, Flaviviridae; 16^(th) InternationalConference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.); p A75)describe the synthesis and pharmacokinetic properties of nucleosideanalogues as possible inhibitors of HCV RNA replication. The authorsreport that 2′-modified nucleosides demonstrate potent inhibitoryactivity in cell-based replicon assays.

Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^(th)International Conference on Antiviral Research (Apr. 27, 2003, Savannah,Ga.) p A76) also described the effects of the 2′-modified nucleosides onHCV RNA replication.

-   -   (11) Other miscellaneous compounds including        1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et        al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.),        vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to        Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat.        No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic        acid, (U.S. Pat. No. 5,830,905 to Diana et al.),        benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.),        polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang        et al.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to        Yarchoan et al.), benzimidazoles (U.S. Pat. No. 5,891,874 to        Colacino et al.), plant extracts (U.S. Pat. No. 5,837,257 to        Tsai et al., U.S. Pat. No. 5,725,859 to Omer et al., and U.S.        Pat. No. 6,056,961), and piperidenes (U.S. Pat. No. 5,830,905 to        Diana et al.).    -   (12) Other compounds currently in preclinical or clinical        development for treatment of hepatitis C virus include:        Interleukin-10 by Schering-Plough, IP-501 by Interneuron,        Merimebodib (VX-497) by Vertex, AMANTADINE® (Symmetrel) by Endo        Labs Solvay, HEPTAZYME® by RPI, IDN-6556 by Idun Pharma.,        XTL-002 by XTL., HCV/MF59 by Chiron, CIVACIR® (Hepatitis C        Immune Globulin) by NABI, LEVOVIRIN® by ICN/Ribapharm,        VIRAMIDINE® by ICN/Ribapharm, ZADAXIN® (thymosin alpha-1) by Sci        Clone, thymosin plus pegylated interferon by Sci Clone, CEPLENE®        (histamine dihydrochloride) by Maxim, VX 950/LY 570310 by        Vertex/Eli Lilly, ISIS 14803 by Isis Pharmaceutical/Elan,        IDN-6556 by Idun Pharmaceuticals, Inc., JTK 003 by AKROS Pharma,        BILN-2061 by Boehringer Ingelheim, CellCept (mycophenolate        mofetil) by Roche, T67, a β-tubulin inhibitor, by Tularik, a        therapeutic vaccine directed to E2 by Innogenetics, FK788 by        Fujisawa Healthcare, Inc., IdB 1016 (Siliphos, oral        silybin-phosphatdylcholine phytosome), RNA replication        inhibitors (VP50406) by ViroPharma/Wyeth, therapeutic vaccine by        Intercell, therapeutic vaccine by Epimmune/Genencor, IRES        inhibitor by Anadys, ANA 245 and ANA 246 by Anadys,        immunotherapy (Therapore) by Avant, protease inhibitor by        Corvas/SChering, helicase inhibitor by Vertex, fusion inhibitor        by Trimeris, T cell therapy by CellExSys, polymerase inhibitor        by Biocryst, targeted RNA chemistry by PTC Therapeutics,        Dication by Immtech, Int., protease inhibitor by Agouron,        protease inhibitor by Chiron/Medivir, antisense therapy by AVI        BioPharma, antisense therapy by Hybridon, hemopurifier by        Aethlon Medical, therapeutic vaccine by Merix, protease        inhibitor by Bristol-Myers Squibb/Axys, Chron-VacC, a        therapeutic vaccine, by Tripep, UT 231B by United Therapeutics,        protease, helicase and polymerase inhibitors by Genelabs        Technologies, IRES inhibitors by Immusol, R803 by Rigel        Pharmaceuticals, INFERGEN® (interferon alphacon-1) by InterMune,        OMNIFERON® (natural interferon) by Viragen, ALBUFERON® by Human        Genome Sciences, REBIF® (interferon beta-1a) by Ares-Serono,        Omega Interferon by BioMedicine, Oral Interferon Alpha by        Amarillo Biosciences, interferon gamma, interferon tau, and        Interferon gamma-1b by InterMune.

Nucleoside prodrugs have been previously described for the treatment ofother forms of hepatitis. WO 00/09531 (filed Aug. 10, 1999) and WO01/96353 (filed Jun. 15, 2001) to Idenix Pharmaceuticals discloses2′-deoxy-β-L-nucleosides and their 3′-prodrugs for the treatment of HBV.U.S. Pat. No. 4,957,924 to Beauchamp discloses various therapeuticesters of acyclovir.

In light of the fact that HCV infection has reached epidemic levelsworldwide, and has tragic effects on the infected patient, there remainsa strong need to provide new effective pharmaceutical agents to treathepatitis C that have low toxicity to the host.

Further, given the rising threat of other flaviviridae infections, thereremains a strong need to provide new effective pharmaceutical agentsthat have low toxicity to the host.

Therefore, it is an object of the present invention to provide acompound, method and composition for the treatment of a host infectedwith hepatitis C virus.

It is another object of the present invention to provide a method andcomposition generally for the treatment of patients infected withpestiviruses, flaviviruses, or hepaciviruses.

SUMMARY OF THE INVENTION

2′ and 3′-prodrugs of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides,or their pharmaceutically acceptable salts or pharmaceuticallyacceptable formulations containing these compounds are useful in theprevention and treatment of Flaviviridae infections and other relatedconditions such as anti-Flaviviridae antibody positive andFlaviviridae-positive conditions, chronic liver inflammation caused byHCV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistenthepatitis, and fatigue. These compounds or formulations can also be usedprophylactically to prevent or retard the progression of clinicalillness in individuals who are anti-Flaviviridae antibody orFlaviviridae-antigen positive or who have been exposed to aFlaviviridae.

A method for the treatment of a Flaviviridae viral infection in a host,including a human, is also disclosed that includes administering aneffective amount of a 2′ or 3′-prodrug of a biologically active 1′, 2′,3′ or 4′-branched β-D or β-L nucleoside or a pharmaceutically acceptablesalt thereof, administered either alone or in combination or alternationwith another anti-Flaviviridae agent, optionally in a pharmaceuticallyacceptable carrier. The term 2′-prodrug, as used herein, refers to a 1′,2′, 3′ or 4′-branched β-D or β-L nucleoside that has a biologicallycleavable moiety at the 2′-position, including, but not limited to acyl,and in one embodiment, a natural or synthetic D or L amino acid,preferably an L-amino acid. The term 3′-prodrug, as used herein, refersto a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside that has abiologically cleavable moiety at the 3′-position, including, but notlimited to acyl, and in one embodiment, a natural or synthetic D or Lamino acid, preferably an L-amino acid.

Pharmaceutically acceptable salts include tosylate, methanesulfonate,acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate, formate, fumarate, propionate,glycolate, lactate, pyruvate, oxalate, maleate, salicyate, sulfate,sulfonate, nitrate, bicarbonate, hydrobromate, hydrobromide,hydroiodide, carbonate, and phosphoric acid salts. A particularlypreferred embodiment is the mono or dihydrochloride salt.

In one embodiment, the 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosideincludes biologically cleavable moieties at the 2′ and/or 5′ positions.Preferred moieties are natural or synthetic D or L amino acid esters,including D or L-valyl, though preferably L-amino acid esters, such asL-valyl, and alkyl esters including acetyl. Therefore, this inventionspecifically includes 2′-D or L-amino acid ester and 2′,5′-D orL-diamino acid ester, preferably L-amino acid ester, of 1′, 2′, 3′ or4′-branched β-D or β-L nucleosides with any desired purine or pyrimidinebase, wherein the parent drug optionally has an EC₅₀ of less than 15micromolar, and even more preferably less than 10 micromolar; 2′-(alkylor aryl) ester or 2′,5′-di(alkyl or aryl) ester of 1′, 2′, 3′ or4′-branched β-D or β-L nucleosides with any desired purine or pyrimidinebase, wherein the parent drug optionally has an EC₅₀ of less than 10 or15 micromolar; and prodrugs of 2′,5′-diesters of 1′, 2′, 3′ or4′-branched β-D or β-L nucleosides wherein (i) the 2′ ester is a naturalor synthetic D or L-amino acid ester, though preferably an L-amino acidester, and the 5′-ester is an alkyl or aryl ester; (ii) both esters areindependently natural or synthetic D or L-amino acid ester, thoughpreferably both are L-amino acid esters; (iii) both esters areindependently alkyl or aryl esters; and (iv) the 2′ ester isindependently an alkyl or aryl ester and the 5′-ester is a natural orsynthetic D or L-amino acid ester, though preferably an L-amino acidester, wherein the parent drug optionally has an EC₅₀ of less than 10 or15 micromolar.

Examples of prodrugs falling within the invention are 2′-D or L-valineester of β-D-2′,6-dimethyl-cytidine; 2′-L-valine ester ofβ-D-2′,6-dimethyl-thymidine; 2′-L-valine ester ofβ-D-2′,8-dimethyl-adenosine; 2′-L-valine ester ofβ-D-2′,8-dimethyl-guanosine; 2′-L-valine ester ofβ-D-2′,6-dimethyl-5-fluorocytidine; 2′-L-valine ester ofβ-D-2′,6-dimethyl-uridine; 2′-acetyl ester ofβ-D-2′,6-dimethyl-cytidine; 2′-acetyl ester ofβ-D-2′,6-dimethyl-thymidine; 2′-acetyl ester ofβ-D-2′,8-dimethyl-adenosine; 2′-acetyl ester ofβ-D-2′,8-dimethyl-guanosine; 2′-acetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 2′-esters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or2′-esters of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine) wherein(i) the 2′ ester is an amino acid ester; or (ii) the 2′ ester is analkyl or aryl ester.

Additional examples of prodrugs falling within the invention are2′,5′-L-divaline ester of β-D-2′,6-dimethyl-cytidine(dival-2′,6-diMe-L-dC); 2′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-thymidine; 2′,5′-L-divaline ester ofβ-D-2′,8-dimethyl-adenosine; 2′,5′-L-divaline ester ofβ-D-2′,8-dimethyl-guanosine; 2′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; 2′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-uridine; 2′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-cytidine; 2′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-thymidine; 2′,5′-diacetyl ester ofβ-D-2′,8-dimethyl-adenosine; 2′,5′-diacetyl ester ofβ-D-2′,8-dimethyl-guanosine; 2′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 2′,5′-diesters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or2′,5′-diesters of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine)wherein (i) the 2′ ester is an amino acid ester and the 5′-ester is analkyl or aryl ester; (ii) both esters are amino acid esters; (iii) bothesters are independently alkyl or aryl esters; or (iv) the 2′ ester isan alkyl or aryl ester and the 5′-ester is an amino acid ester.

In another embodiment, the 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleoside 3′-prodrug includes biologically cleavable moieties at the 3′and/or 5′ positions. Preferred moieties are natural or synthetic D or Lamino acid esters, such as valyl, though preferably L-amino acids, suchas L-valyl, and alkyl esters including acetyl. Therefore, this inventionspecifically includes 3′-L-amino acid ester and 3′,5′-L-diamino acidester of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides with anydesired purine or pyrimidine base, wherein the parent drug optionallyhas an EC₅₀ of less than 15 micromolar, and even more preferably lessthan 10 micromolar; 3′-(alkyl or aryl) ester or 3′,5′-L-di(alkyl oraryl) ester of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides with anydesired purine or pyrimidine base, wherein the parent drug optionallyhas an EC₅₀ of less than 10 or 15 micromolar; and prodrugs of3′,5′-diesters of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosideswherein (i) the 3′ ester is a natural or synthetic D or L amino acidester and the 5′-ester is an alkyl or aryl ester, (ii) both esters arenatural or synthetic D or L-amino acid esters; (iii) both esters areindependently alkyl or aryl esters; and (iv) the 3′ ester isindependently an alkyl or aryl ester and the 5′-ester is a natural orsynthetic D or L-amino acid ester, wherein the parent drug optionallyhas an EC₅₀ of less than 10 or 15 micromolar.

Examples of prodrugs falling within the invention are 3′-L-valine esterof β-D-2′,6-dimethyl-cytidine; 3′-L-valine ester ofβ-D-2′,6-dimethyl-thymidine; 3′-L-valine ester ofβ-D-2′,8-dimethyl-adenosine; 3′-L-valine ester ofβ-D-2′,8-dimethyl-guanosine; 3′-L-valine ester ofβ-D-2′,6-dimethyl-5-fluorocytidine; 3′-L-valine ester ofβ-D-2′,6-dimethyl-uridine; 3′-acetyl ester ofβ-D-2′,6-dimethyl-cytidine; 3′-acetyl ester ofβ-D-2′,6-dimethyl-thymidine; 3′-acetyl ester ofβ-D-2′,8-dimethyl-adenosine; 3′-acetyl ester ofβ-D-2′,8-dimethyl-guanosine; 3′-acetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 3′-esters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or3′-esters of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine) wherein(i) the 3′ ester is an amino acid ester; or (ii) the 3′ ester is analkyl or aryl ester.

Additional examples of prodrugs falling within the invention are3′,5′-L-divaline ester of β-D-2′,6-dimethyl-cytidine(dival-2′,6-diMe-L-dC); 3′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-thymidine; 3′,5′-L-divaline ester ofβ-D-2′,8-dimethyl-adenosine; 3′,5′-L-divaline ester ofβ-D-2′,8-dimethyl-guanosine; 3′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; 3′,5′-L-divaline ester ofβ-D-2′,6-dimethyl-uridine; 3′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-cytidine; 3′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-thymidine; 3′,5′-diacetyl ester ofβ-D-2′,8-dimethyl-adenosine; 3′,5′-diacetyl ester ofβ-D-2′,8-dimethyl-guanosine; 3′,5′-diacetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 3′,5′-diesters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or3′,5′-diesters of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine)wherein (i) the 3′ ester is an amino acid ester and the 5′-ester is analkyl or aryl ester; (ii) both esters are amino acid esters; (iii) bothesters are independently alkyl or aryl esters; or (iv) the 3′ ester isan alkyl or aryl ester and the 5′-ester is an amino acid ester.

In another embodiment, the prodrug of 1′, 2′, 3′ or 4′-branched β-D orβ-L nucleoside includes biologically cleavable moieties at the 2′, 3′and/or 5′ positions. Preferred moieties are natural or synthetic D or Lamino acid esters, including D or L-valyl, though preferably L-aminoacid esters, such as L-valyl, and alkyl esters including acetyl.Therefore, this invention specifically includes 2′,3′-L or D-diaminoacid ester and 2′,3′,5′-L or D-triamino acid ester of 1′, 2′, 3′ or4′-branched β-D or β-L nucleosides, preferrably L-amino acid, with anydesired purine or pyrimidine base, wherein the parent drug optionallyhas an EC₅₀ of less than 15 micromolar, and even more preferably lessthan 10 micromolar; 2′,3′-di(alkyl or aryl) ester or2′,3′,5′-L-tri(alkyl or aryl) ester of 1′, 2′, 3′ or 4′-branched β-D orβ-L nucleosides with any desired purine or pyrimidine base, wherein theparent drug optionally has an EC₅₀ of less than 10 or 15 micromolar; andprodrugs of 2′,3′-diesters of 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleosides wherein (i) the 2′ ester is an amino acid ester and the3′-ester is an alkyl or aryl ester; (ii) both esters are amino acidesters; (iii) both esters are independently alkyl or aryl esters; and(iv) the 2′ ester is independently an alkyl or aryl ester and the3′-ester is an amino acid ester, wherein the parent drug optionally hasan EC₅₀ of less than 10 or 15 micromolar. Further, 2′,3′,5′-triesters of1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides wherein (i) all threeesters are amino acid esters; (ii) all three esters are independentlyalkyl or aryl esters; (iii) the 2′ ester is an amino acid ester, the 3′ester is an amino acid ester and the 5′-ester is an alkyl or aryl ester;(iv) the 2′ ester is an amino acid ester, the 3′ ester is an alkyl oraryl ester and the 5′-ester is an alkyl or aryl ester; (v) the 2′ esteris an alkyl or aryl ester, the 3′ ester is an alkyl or aryl ester andthe 5′-ester is an amino acid ester; (vi) the 2′ ester is an alkyl oraryl ester, the 3′ ester is an amino acid ester and the 5′-ester is anamino acid ester; (vii) the 2′ ester is an alkyl or aryl ester, the 3′ester is an amino acid ester and the 5′-ester is an alkyl or aryl ester;and (viii) the 2′ ester is an amino acid ester, the 3′ ester is an alkylor aryl ester and the 5′-ester is an amino acid ester; wherein theparent drug optionally has an EC₅₀ of less than 10 or 15 micromolar.

Examples of prodrugs falling within the invention include2′,3′-L-divaline ester of β-D-2′,6-dimethyl-cytidine(dival-2′,6-diMe-L-dC); 2′,3′-L-divaline ester ofβ-D-2′,6-dimethyl-thymidine; 2′,3′-L-divaline ester ofβ-D-2′,8-dimethyl-adenosine; 2′,3′-L-divaline ester ofβ-D-2′,8-dimethyl-guanosine; 2′,3′-L-divaline ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; 2′,3′-L-divaline ester ofβ-D-2′,6-dimethyl-uridine; 2′,3′-diacetyl ester ofβ-D-2′,6-dimethyl-cytidine; 2′,3′-diacetyl ester ofβ-D-2′,6-dimethyl-thymidine; 2′,3′-diacetyl ester ofβ-D-2′,8-dimethyl-adenosine; 2′,3′-diacetyl ester ofβ-D-2′,8-dimethyl-guanosine; 2′,3′-diacetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 2′,3′-diesters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) or2′,3′-diesters of β-D-2′,8-dimethyl-(guanosine, adenosine or inosine)wherein (i) the 2′ ester is an amino acid ester and the 3′-ester is analkyl or aryl ester; (ii) both esters are amino acid esters; (iii) bothesters are independently alkyl or aryl esters; or (iv) the 2′ ester isan alkyl or aryl ester and the 3′-ester is an amino acid ester.

Additional examples of prodrugs falling within the invention include2′,3′,5′-L-trivaline ester of β-D-2′,6-dimethyl-cytidine(trival-2′,6-diMe-L-dC); 2′,3′,5′-L-trivaline ester ofβ-D-2′,6-dimethyl-thymidine; 2′,3′,5′-L-trivaline ester ofβ-D-2′,8-dimethyl-adenosine; 2′,3′,5′-L-trivaline ester ofβ-D-2′,8-dimethyl-guanosine; 2′,3′,5′-L-trivaline ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; 2′,3′,5′-L-trivaline ester ofβ-D-2′,6-dimethyl-uridine; 2′,3′,5′-triacetyl ester ofβ-D-2′,6-dimethyl-cytidine; 2′,3′,5′-triacetyl ester ofβ-D-2′,6-dimethyl-thymidine; 2′,3′,5′-triacetyl ester ofβ-D-2′,8-dimethyl-adenosine; 2′,3′,5′-triacetyl ester ofβ-D-2′,8-dimethyl-guanosine; 2′,3′,5′-triacetyl ester ofβ-D-2′,6-dimethyl-5-fluoro-cytidine; and 2′,3′,5′-triesters ofβ-D-2′,6-dimethyl-(cytidine, 5-fluorocytidine, uridine or thymidine) and2′,3′,5′-triesters of β-D-2′,8-dimethyl-(guanosine, adenosine orinosine) wherein (i) all three esters are amino acid esters; (ii) allthree esters are independently alkyl or aryl esters; (iii) the 2′ esteris an amino acid ester, the 3′ ester is an amino acid ester and the5′-ester is an alkyl or aryl ester; (iv) the 2′ ester is an amino acidester, the 3′ ester is an alkyl or aryl ester and the 5′-ester is analkyl or aryl ester; (v) the 2′ ester is an alkyl or aryl ester, the 3′ester is an alkyl or aryl ester and the 5′-ester is an amino acid ester;(vi) the 2′ ester is an alkyl or aryl ester, the 3′ ester is an aminoacid ester and the 5′-ester is an amino acid ester; (vii) the 2′ esteris an alkyl or aryl ester, the 3′ ester is an amino acid ester and the5′-ester is an alkyl or aryl ester; and (viii) the 2′ ester is an aminoacid ester, the 3′ ester is an alkyl or aryl ester and the 5′-ester isan amino acid ester.

In a first principal embodiment, a compound of Formula (I) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate); straight chained, branched orcyclic alkyl (including lower alkyl); acyl (including lower acyl);CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl,sulfonate ester including alkyl or arylalkyl sulfonyl includingmethanesulfonyl and benzyl, wherein the phenyl group is optionallysubstituted with one or more substituents as described in the definitionof aryl given herein; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alipid, including a phospholipid; an amino acid; and amino acid residue,a carbohydrate; a peptide; cholesterol; or other pharmaceuticallyacceptable leaving group which is capable of providing a compoundwherein R¹, R² and/or R³ is independently H or phosphate (includingmono-, di- or triphosphate), for example when administered in vivo;wherein in one embodiment R² and/or R³ is not phosphate (includingmono-, di- or triphosphate or a stabilized phosphate prodrug);wherein at least one of R² and R³ is not hydrogen; and wherein:Y¹ is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR⁴, NH₂, NHR⁴,NR⁴R⁵, SH or SR⁴;X¹ is a straight chained, branched or cyclic optionally substitutedalkyl, CH₃, CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, CH₂OH, optionally substituted alkenyl, optionallysubstituted alkynyl, COOH, COOR⁴, COO-alkyl, COO-aryl, CO-Oalkoxyalkyl,CONH₂, CONHR⁴, CON(R⁴)₂, chloro, bromo, fluoro, iodo, CN, N₃, OH, OR⁴,NH₂, NHR⁴, NR⁴R⁵, SH or SR⁵; andX² is H, straight chained, branched or cyclic optionally substitutedalkyl, CH₃, CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, CH₂OH, optionally substituted alkenyl, optionallysubstituted alkynyl, COOH, COOR⁴, COO-alkyl, COO-aryl, CO-Oalkoxyalkyl,CONH₂, CONHR⁴, CON(R⁴)₂, chloro, bromo, fluoro, iodo, CN, N₃, OH, OR⁴,NH₂, NHR⁴, NR⁴R⁵, SH or SR⁵; andwherein each Y³ is independently H, F, Cl, Br or I;each R⁴ and R⁵ is independently hydrogen, acyl (including lower acyl),alkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl), lower alkyl, alkenyl, alkynyl or cycloalkyl.

In the embodiments described herein, R¹, R² and/or R³ may be apharmaceutically acceptable leaving group which is capable of providinga compound wherein R¹, R² and/or R³ is independently H or phosphate(including mono-, di- or triphosphate), for example when administered invivo.

In a second principal embodiment, a compound of Formula (II) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (II):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R², R³, R⁴, R⁵, Y¹, Y³, X¹ and X² are as defined above.

In a third principal embodiment, a compound of Formula (III), (IV) or(V), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric, or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (III), (IV) or (V):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:Base is selected from the group consisting of

R¹, R² R³, R⁴, and R⁵, are as defined above;each W¹, W², W³ and W⁴ is independently N, CH, CF, CI, CBr, CCl, CCN,CCH₃, CCF₃, CCH₂CH₃, CC(O)NH₂, CC(O)NHR⁴, CC(O)N(R⁴)₂, CC(O)OH, CC(O)OR⁴or CX³;each W* is independently O, S, NH or NR⁴;X is O, S, SO₂, CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ orC(R⁴)₂;X* is CH, CF, CY³ or CR⁴;X² is H, straight chained, branched or cyclic optionally substitutedalkyl, CH₃, CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, CH₂OH, optionally substituted alkenyl, optionallysubstituted alkynyl, COOH, COOR⁴, COO-alkyl, COO-aryl, CO-Oalkoxyalkyl,CONH₂, CONHR⁴, CON(R⁴)₂, chloro, bromo, fluoro, iodo, CN, N₃, OH, OR⁴,NH₂, NHR⁴, NR⁴R⁵, SH or SR⁵;each X³ is independently a straight chained, branched or cyclicoptionally substituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (includinghalogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃,CF₂CF₃, C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl,Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃, CN, —C(O)OH,—C(O)OR⁴, —C(O)O(lower alkyl), —C(O)NH₂, —C(O)NHR⁴, —C(O)NH(loweralkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂, OH, OR⁴, —O(acyl), —O(loweracyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl),—O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R⁴), —S(loweralkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), chloro,bromo, fluoro, iodo, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵, —NH(acyl),—N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂;each Y is independently selected from the group consisting of H,optionally substituted lower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃,CF₂CF₃, CH₂CO₂R, (CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CONH₂,(CH₂)_(m)CONR₂, and (CH₂)_(m)CONHR;wherein R is H, alkyl or acyl;Y¹ is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR⁴, NH₂, NHR⁴,NR⁴R⁵, SH or SR⁴;each Y² is independently O, S, NH or NR⁴;each Y³ is independently H, F, Cl, Br or I;wherein for Base (B), W⁴ cannot be CH if W¹, W² and W³ are N;wherein for Base (E), (F), (K), (L), (W) and (X), W⁴ cannot be CH if W¹is N;each R⁶ is independently an optionally substituted alkyl (includinglower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH,halogenated alkyl (including halogenated lower alkyl), CF₃, C(Y³)₃,2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, optionallysubstituted alkenyl, haloalkenyl, Br-vinyl, optionally substitutedalkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl),—CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂,—CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴,—(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴,—(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂ or cyano;each R⁷ is independently OH, OR², optionally substituted alkyl(including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR³, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);alternatively, R⁶ and R⁷ can come together to form a spiro compoundselected from the group consisting of optionally substituted carbocycle(preferably a 3-7 membered carbocyclic ring) or optionally substitutedheterocycle (preferably a 3-7 membered heterocyclic ring having one ormore O, S and/or N); andeach m is independently 0, 1 or 2.

In a fourth principal embodiment, a compound of Formula (VI) or (VII),or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (VI)or (VII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:Base, R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Y, Y¹, Y², Y³, W¹, W², W³, W⁴, W*,X, X*, X¹, X², and X³ are as defined above;wherein, in one embodiment, R⁸ in Formula (VI) is —OH or —NH₂ only whenX is carbon;and wherein;each R⁸ and R¹¹ is independently hydrogen, an optionally substitutedalkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(loweralkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH,—(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂,—(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂, cyano, NH-acyl or N(acyl)₂;each R⁹ and R¹⁰ are independently hydrogen, OH, OR², optionallysubstituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenatedlower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);each m is independently 0, 1 or 2; andalternatively, R⁶ and R¹⁰, R⁷ and R⁹, R⁸ and R⁷ or R⁹ and R¹¹ can cometogether to form a bridged compound selected from the group consistingof optionally substituted carbocycle (preferably a 3-7 memberedcarbocyclic ring) or optionally substituted heterocycle (preferably a3-7 membered heterocyclic ring having one or more O, S and/or N); oralternatively, R⁶ and R⁷ or R⁹ and R¹⁰ can come together to form a spirocompound selected from the group consisting of optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring) or optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N).

In a fifth principal embodiment, a compound of Formula (VIII), (IX) or(X), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (VIII), (IX) or (X):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R², R³, R⁴, R⁵, X, Y³, and X* are as defined above;Base* is a purine or pyrimidine base as defined herein;each R¹² is independently a substituted alkyl (including lower alkyl),CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl(including halogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F,CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, substituted alkenyl, haloalkenyl(but not Br-vinyl), substituted alkynyl, haloalkynyl, —CH₂C(O)OH,—CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂;each R¹³ is independently substituted alkyl (including lower alkyl),CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl(including halogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F,CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, substituted alkenyl, haloalkenyl(but not Br-vinyl), substituted alkynyl, haloalkynyl, optionallysubstituted carbocycle (preferably a 3-7 membered carbocyclic ring),optionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N), optionallysubstituted heteroaryl (preferably a 3-7 membered heteroaromatic ringhaving one or more O, S and/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)SH, —CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl),—CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂,—CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴,—(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴,—(CH₂)_(m)C(O)S(lower alkyl), —(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴,—(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)SH, —C(O)SR⁴,—C(O)S(lower alkyl), —C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl),—C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂, —O(R⁴), —O(alkynyl), —O(aralkyl),—O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R⁴), —S(lower alkyl),—S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), —NHR⁴, —NR⁴R⁵,—NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), SCN, OCN, NCOor fluoro;alternatively, R¹² and R¹³ can come together to form a spiro compoundselected from the group consisting of optionally substituted carbocycle(preferably a 3-7 membered carbocyclic ring) or optionally substitutedheterocycle (preferably a 3-7 membered heterocyclic ring having one ormore O, S and/or N); andeach m is independently 0, 1 or 2.

In a sixth principal embodiment, a compound of Formula (XI) or (XII), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (XI)or (XII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:alternatively, Base*, is replaced with Base in Formulas (XI) and (XII);andBase, Base*, R, R¹, R², R³, R⁴, R⁵, R¹², R¹³, Y, Y¹, Y², Y³, W*, W¹, W²,W³, W⁴, X, X*, X¹, X², and X³ are as defined above;wherein, in one embodiment, R⁸ in Formula (XI) is —OH or —NH₂ only whenX is carbon; andwherein;each R⁸ and R¹¹ is independently hydrogen, an optionally substitutedalkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(loweralkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH,—(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂,—(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂, cyano, NH-acyl or N(acyl)₂;each R⁹ and R¹⁰ are independently hydrogen, OH, OR², optionallysubstituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenatedlower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);each m is independently 0, 1 or 2; andalternatively, R⁸ and R¹³, R⁹ and R¹³, R⁹ and R¹¹ or R¹⁰ and R¹² cancome together to form a bridged compound selected from the groupconsisting of optionally substituted carbocycle (preferably a 3-7membered carbocyclic ring) or optionally substituted heterocycle(preferably a 3-7 membered heterocyclic ring having one or more O, Sand/or N); or alternatively, R¹² and R¹³ or R⁹ and R¹⁰ can come togetherto form a spiro compound selected from the group consisting ofoptionally substituted carbocycle (preferably a 3-7 membered carbocyclicring) or optionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N).

In a particular aspect of the invention, a compound of Formula (XI) or(XII), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (XI) or (XII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R₃ is selected from the group consisting of H; mono-, di-, andtri-phosphate or a stabilized phosphate prodrug; acyl; a sulfonateester; optionally substituted alkyl sulfonyl; optionally substitutedarylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide;cholesterol; and a pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R₃ isindependently H, or mono-, di- or triphosphate;X″ is selected from the group consisting of one or more O, S, SO, SO₂,N, NH, NR and CH₂ wherein any of the aforementioned may be optionallysubstituted and may be variably positioned so as to form a 3-7 memberedring;R is H, alkyl or acyl; andB indicates a spiro compound selected from the group consisting ofoptionally substituted carbocycle (preferably a 3-7 membered carbocyclicring) or optionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N);Base is selected from the group consisting of:

-   -   wherein:    -   each R′, R″, R′″ and R″″ are independently selected from the        group consisting of H, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,        O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, O-cycloalkyl,        NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl,        S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂, CO₂-alkyl, CONH-alkyl,        CON-dialkyl, OH, CF₃, CH₂OH, (CH₂)_(m)OH, (CH₂)_(m)NH₂,        (CH₂)_(m)COOH, (CH₂)_(m)CN, (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;    -   m is 0 or 1;    -   W is C—R″ or N;    -   T and V independently are CH or N;    -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or N;    -   Q₁ and Q₂ independently are N or C—R;    -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and    -   tautomeric forms thereof.

In a second particular aspect of the invention, a compound of Formula(XV), (XVI) or (XVII), or a pharmaceutically acceptable salt or prodrug,or a stereoisomeric, tautomeric or polymorphic form thereof, isprovided, as well as a method for the treatment of a host infected witha Flaviviridae comprising administering an effective treatment amount ofcompound of Formula (XV), (XVI) or (XVII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:G and E independently are selected from the group consisting of CH₃,CH₂OH, CH₂F, CH₂N₃, CH₂CN, (CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CONH₂,(CH₂)_(m)CONR₂, (CH₂)_(m)CONHR and N-acyl;m is 0 or 1;R is H, alkyl or acyl; andR′, R″, R′″, R″″, and R³ and Base are as defined for Formula (XIII).

Alternatively, for compound of Formula (XVII), at most one of G and Ecan further be hydrogen.

In a third particular aspect of the invention, a compound of Formula(XVIII) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (XVIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, whereinM is selected from the group consisting of S, SO, and SO₂; andR′, R″, R′″, R″″, and R₃ and Base are as defined for Formula (XIII).

In a fourth particular aspect of the invention, a compound of Formula(XIX), (XX), (XXI) (XXII) or (XXIII) or a pharmaceutically acceptablesalt or prodrug, or a stereoisomeric, tautomeric or polymorphic formthereof, is provided, as well as a method for the treatment of a hostinfected with a Flaviviridae comprising administering an effectivetreatment amount of compound of Formula (XIX), (XX), (XXI) (XXII) or(XXIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof wherein:A is selected from the group consisting of optionally substituted loweralkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R,(CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CO—NH₂, (CH₂)_(m)CONR₂, and(CH₂)_(m)CONHR;Y is selected from the group consisting of H, optionally substitutedlower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R,(CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CONH₂, (CH₂)_(m)CONR₂, and(CH₂)_(m)CONHR;X is selected from the group consisting of —OH, optionally substitutedalkyl, cycloalkyl, alkenyl, alkynyl, —O-alkyl, —O-alkenyl, —O-alkynyl,—O-aryl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN,OCN, NCO, NO₂, NH₂, N₃, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl,NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl,S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂-alkyl,CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl,CONH-cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl,CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R, (CH₂)_(m)COOH,(CH₂)_(m)COOR, (CH₂)_(m)CONH₂, (CH₂)_(m)CONR₂, (CH₂)_(m)CONHR, anoptionally substituted 3-7 membered carbocyclic, and an optionallysubstituted 3-7 membered heterocyclic ring having O, S and/or Nindependently as a heteroatom taken alone or in combination;m is 0 or 1;R is H, alkyl or acyl;R₃ is selected from the group consisting of H; mono-, di-, andtri-phosphate or a stabilized phosphate prodrug; substituted orunsubstituted alkyl; acyl; a sulfonate ester, optionally substitutedalkyl sulfonyl; optionally substituted arylsulfonyl; a lipid; an aminoacid; a carbohydrate; a peptide; cholesterol; and a pharmaceuticallyacceptable leaving group which when administered in vivo is capable ofproviding a compound wherein R₃ is independently H, or mono-, di- ortriphosphate; andBase is a non-natural base selected from the group of:

or (i) herein below

-   -   wherein:    -   each R′, R″, R′″ and R″″ is independently selected from the        group consisting of H, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,        O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, O-cycloalkyl,        NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl,        S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂, CO₂-alkyl, CONH-alkyl,        CON-dialkyl, OH, CF₃, CH₂OH, (CH₂)_(m)OH, (CH₂)_(m)NH₂,        (CH₂)_(m)COOH, (CH₂)_(m)CN, (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;    -   m is 0 or 1;    -   W is C—R″ or N;    -   T and V independently are CH or N;    -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or N;    -   Q₁ and Q₂ independently are N or C—R″″; and    -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH;    -   with the proviso that in bases (g) and (i), R′, R″″ are not H,        OH, or NH₂; and Q, T, V, Q₂, Q₅ and Q₆ are not N.

In one embodiment, the amino acid residue is of the formulaC(O)C(R¹¹)(R¹²)(NR¹³R¹⁴), wherein:

R¹¹ is the side chain of an amino acid and wherein, as in proline, R¹¹can optionally be attached to R¹³ to form a ring structure; oralternatively, R¹¹ is an alkyl, aryl, heteroaryl or heterocyclic moiety;R¹² is hydrogen, alkyl (including lower alkyl) or aryl; andR¹³ and R¹⁴ are independently hydrogen, acyl (including an acylderivative attached to R¹¹) or alkyl (including but not limited tomethyl, ethyl, propyl, and cyclopropyl).

In another preferred embodiment, at least one of R² and R³ is an aminoacid residue, and is preferably L-valinyl.

The β-D- and β-L-nucleosides of this invention may inhibit Flaviviridaepolymerase activity. Nucleosides can be screened for their ability toinhibit Flaviviridae polymerase activity in vitro according to screeningmethods set forth more particularly herein. One can readily determinethe spectrum of activity by evaluating the compound in the assaysdescribed herein or with another confirmatory assay.

In one embodiment the efficacy of the anti-Flaviviridae compound ismeasured according to the concentration of compound necessary to reducethe plaque number of the virus in vitro, according to methods set forthmore particularly herein, by 50% (i.e. the compound's EC₅₀). Inpreferred embodiments the parent of the prodrug compound exhibits anEC₅₀ of less than 25, 15, 10, 5, or 1 micromolar. In preferredembodiments the compound exhibits an EC₅₀ of less than 15 or 10micromolar, when measured according to the polymerase assay described inFerrari et al., Jnl. of Vir., 73:1649-1654, 1999; Ishii et al.,Hepatology, 29:1227-1235, 1999; Lohmann et al., Jnl. of Bio. Chem.,274:10807-10815, 1999; or Yamashita et al, Jnl. of Bio. Chem.,273:15479-15486, 1998.

In another embodiment, combination and/or alternation therapy areprovided. In combination therapy, an effective dosage of two or moreagents are administered together, whereas during alternation therapy aneffective dosage of each agent is administered serially. The dosageswill depend on absorption, inactivation, and excretion rates of the drugas well as other factors known to those of skill in the art. It is to benoted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens and schedules should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions.

The invention provides combinations of at least two of the hereindescribed prodrugs. The invention further provides at least one of thedescribed 2′ and 3′-prodrugs in combination or alternation with a secondnucleoside that exhibits activity against a Flaviviridae, including butnot limited to a parent drug of any of the prodrugs defined herein, i.e.β-D-2′,6-dimethyl-cytidine, β-D-2′,6-dimethyl-thymidine,β-D-2′,8-dimethyl-adenosine, β-D-2′,8-dimethyl-guanosine,β-D-2′,6-dimethyl-5-fluorocytidine and/or β-D-2′,6-dimethyl-uridine.Alternatively, the 2′ or 3′-prodrugs can be administered in combinationor alternation with other anti-Flaviviridae agent exhibits an EC₅₀ ofless than 10 or 15 micromolar, or their prodrugs or pharmaceuticallyacceptable salts.

Nonlimiting examples of antiviral agents that can be used in combinationwith the compounds disclosed herein include: 1) an interferon and/orribavirin; (2) Substrate-based NS3 protease inhibitors; (3)Non-substrate-based inhibitors; (4) Thiazolidine derivatives; (5)Thiazolidines and benzanilides; (6) A phenan-threnequinone; (7) NS3inhibitors; (8) HCV helicase inhibitors; (9) polymerase inhibitors,including RNA-dependent RNA-polymerase inhibitors; (10) Antisenseoligodeoxynucleotides; (11) Inhibitors of IRES-dependent translation;(12) Nuclease-resistant ribozymes; and (13) other compounds that exhibitactivity against a flaviviridae. The invention further includesadministering the prodrug in combination or alternation with an immunemodulator or other pharmaceutically active modifier of viralreplication, including a biological material such as a protein, peptide,oligonucleotide, or gamma globulin, including but not limited tointerferon, interleukin, or an antisense oligonucleotides to genes whichexpress or regulate Flaviviridae replication.

The invention further includes administering the prodrug in combinationor alternation with an immune modulator or other pharmaceutically activemodifier of viral replication, including a biological material such as aprotein, peptide, oligonucleotide, or gamma globulin, including but notlimited to interferon, interleukin, or an antisense oligonucleotides togenes which express or regulate Flaviviridae replication.

In particular, the present invention provides the following:

-   (a) a compound of Formula (XIII)-(XXIII), or its pharmaceutically    acceptable salt or prodrug thereof;-   (b) pharmaceutical compositions comprising a compound of Formula    (XIII)-(XXIII), or its pharmaceutically acceptable salt or prodrug    thereof, together with a pharmaceutically acceptable carrier or    diluent;-   (c) pharmaceutical compositions comprising a compound of Formula    (XIII)-(XXIII), or its pharmaceutically acceptable salt or prodrug    thereof, with one or more other effective antiviral agent,    optionally with a pharmaceutically acceptable carrier or dileuent;-   (d) pharmaceutical compositions for the treatment of a Flaviviridae    infection in a host comprising a compound of Formula (I)-(XXIII), or    its pharmaceutically acceptable salt or prodrug thereof, together    with a pharmaceutically acceptable carrier or dileuent;-   (e) pharmaceutical compositions for the treatment of a Flaviviridae    infection in a host comprising a compound of Formula (I)-(XXIII), or    its pharmaceutically acceptable salt or prodrug thereof, with one or    more other effective antiviral agent, optionally with a    pharmaceutically acceptable carrier or dileuent;-   (f) methods for the treatment of a Flaviviridae infection in a host    comprising a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, optionally with    a pharmaceutically acceptable carrier or dileuent;-   (g) methods for the treatment of a Flaviviridae infection in a host    comprising a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, with one or    more other effective antiviral agent, optionally with a    pharmaceutically acceptable carrier or dileuent;-   (h) uses for a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, optionally with    a pharmaceutically acceptable carrier or dileuent, for the treatment    of a Flaviviridae infection in a host;-   (i) uses for a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, with one or    more other effective antiviral agent, optionally with a    pharmaceutically acceptable carrier or dileuent, for the treatment    of a Flaviviridae infection in a host;-   (j) uses for a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, optionally with    a pharmaceutically acceptable carrier or dileuent, in the    manufacture of a medicament for the treatment of a Flaviviridae    infection in a host; and-   (k) uses for a compound of Formula (I)-(XXIII), or its    pharmaceutically acceptable salt or prodrug thereof, with one or    more other effective antiviral agent, optionally with a    pharmaceutically acceptable carrier or dileuent, in the manufacture    of a medicament for the treatment of a Flaviviridae infection in a    host.

In an alternative embodiment, the parent nucleoside compound of any ofthe 2′- or 3′-prodrugs (i.e., the nucleosides without the 2′- or3′-cleavable moieties) are provided for the treatment of a Flaviviridaeinfection and in particular a hepatitis C infection.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides the structure of various non-limiting examples ofnucleosides of the present invention, as well as other knownnucleosides, in particular FIAU and ribavirin.

FIG. 2 provides a non-limiting example of the steps involved inesterification of the 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside toobtain a 2′-prodrug. The same general procedure can be used to obtainthe 3′-prodrug by selectively protecting the 2′ and 5′-hydroxyl groupsor protecting the 2′, 3′ and 5′-hydroxyl groups and selectivelydeprotecting the 3′-hydroxyl.

FIG. 3 provides a non-limiting example of the steps involved inesterification of the 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside toobtain a 3′-prodrug.

FIG. 4 provides a non-limiting example of the steps involved inesterification of the 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside toobtain a 2′,3′-prodrug.

DETAILED DESCRIPTION OF THE INVENTION

The invention as disclosed herein is a compound, a method andcomposition for the treatment of a Flaviviridae infection in humans andother host animals. The method includes the administration of aneffective anti-Flaviviridae treatment amount of a 2′ and/or 3′-prodrugof a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside as described hereinor a pharmaceutically acceptable salt, derivative or prodrug thereof,optionally in a pharmaceutically acceptable carrier. The compounds ofthis invention either possesses antiviral (i.e., anti-HCV) activity, orare metabolized to a compound that exhibits such activity. HCV is amember of the Flaviviridae family. HCV has been placed in a newmonotypic genus, hepacivirus. Therefore, in one embodiment, theFlaviviridae is HCV. In an alternate embodiment, the Flaviviridae is aflavivirus or pestivirus.

The 2′ and/or 3′-prodrugs of a 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleoside are acyl derivates of a secondary or tertiary alcohol alphato a secondary or tertiary carbon. Due to the steric hindrance of theseprodrugs over the 5′-prodrugs, an acyl derivative of a primary alcohol,these prodrugs differentially modulate the biological properties of themolecule in vivo. It has been discovered that the 2′ and/or 3′-prodrugsof a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside can provide a drugwith increased half-life and improved pharmacokinetic profile.

The 2′ or 3′-prodrug in a preferred embodiment is a cleavable acylgroup, and most particularly, an amino acid moiety, prepared from anynaturally occurring and synthetic α, β γ or δ amino acid, including butis not limited to, glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. In one particular, embodiment, the moiety is a valineester. On particularly preferred compound is the 3′-valine ester of2′,6-dimethyl-ribo-cytidine.

The oral bio-availability of 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleoside as the neutral base and the HCl salt is low in rodents andnon-human primates. It has been discovered that there is significantcompetition of 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside withother nucleosides or nucleoside analogs for absorption, or transport,from the gastrointestinal tract and competition of other nucleosides ornucleoside analogs for the absorption with 1′, 2′, 3′ or 4′-branched β-Dor β-L nucleoside. In order to improve oral bioavailability and reducethe potential for drug-drug interaction, 2′ and 3′-prodrugs of 1′, 2′,3′ or 4′-branched β-D or β-L nucleoside were obtained with higher oralbioavailability than the parent molecule and a reduced effect on thebioavailability of other nucleosides or nucleoside analogs used incombination.

The 2′, 3′, and/or 5′-mono, di or trivaline ester of a 1′, 2′, 3′ or4′-branched β-D or β-L nucleoside have higher oral bioavailability thanthe parent 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside and reducedinteraction with other nucleosides or nucleoside analogs when used incombination as compared to 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleoside.

The 2′, 3′, and/or 5′-mono, di or trivaline ester of a 1′, 2′, 3′ or4′-branched β-D or β-L nucleoside can be converted to the parent 1′, 2′,3′ or 4′-branched β-D or β-L nucleoside through de-esterification in thegastrointestinal mucosa, blood or liver. The 2′, 3′, and/or 5′-mono, dior trivaline ester of a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosidecan be actively transported from the gastrointestinal lumen after oraldelivery into the bloodstream by an amino acid transporter function inthe mucosa of the gastrointestinal tract. This accounts for the increasein oral bioavailability compared to the parent 1′, 2′, 3′ or 4′-branchedβ-D or β-L nucleoside that is transported primarily by a nucleosidetransporter function. There is also reduced competition for uptake ofthe 2′, 3′, and/or 5′-mono, di or trivaline ester of 1′, 2′, 3′ or4′-branched β-D or β-L nucleoside with other nucleosides or nucleosideanalogs that are transported by the nucleoside transporter function andnot the amino acid transporter function. As partial de-esterification ofthe di or trivaline ester of 1′, 2′, 3′ or 4′-branched β-D or β-Lnucleoside occurs prior to complete absorption, the mono or divalineester continues to be absorbed using the amino acid transporterfunction. Therefore, the desired outcome of better absorption, orbioavailability, and reduced competition with other nucleosides ornucleoside analogs for uptake into the bloodstream can be maintained.

In summary, the present invention includes the following features:

-   (a) a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D or β-L    nucleoside, as described herein, and pharmaceutically acceptable    salts and compositions thereof;-   (b) a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D or β-L    nucleoside as described herein, and pharmaceutically acceptable    salts and compositions thereof for use in the treatment and/or    prophylaxis of a Flaviviridae infection, especially in individuals    diagnosed as having a Flaviviridae infection or being at risk of    becoming infected by hepatitis C;-   (c) a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D or β-L    nucleoside, or their pharmaceutically acceptable salts and    compositions as described herein substantially in the absence of the    opposite enantiomers of the described nucleoside, or substantially    isolated from other chemical entities;-   (d) processes for the preparation of a 2′ and/or 3′-prodrug of a 1′,    2′, 3′ or 4′-branched β-D or β-L nucleoside, as described in more    detail below;-   (c) pharmaceutical formulations comprising a 2′ and/or 3′-prodrug of    a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside or a    pharmaceutically acceptable salt thereof together with a    pharmaceutically acceptable carrier or diluent;-   (f) pharmaceutical formulations comprising a 2′ and/or 3′-prodrug of    a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside or a    pharmaceutically acceptable salt thereof together with one or more    other effective anti-HCV agents, optionally in a pharmaceutically    acceptable carrier or diluent;-   (g) pharmaceutical formulations comprising a 2′ and/or 3′-prodrug of    a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside or a    pharmaceutically acceptable salt thereof together with the parent of    a different a 1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside,    optionally in a pharmaceutically acceptable carrier or diluent;-   (h) a method for the treatment and/or prophylaxis of a host infected    with Flaviviridae that includes the administration of an effective    amount of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, its pharmaceutically acceptable salt or    composition;-   (i) a method for the treatment and/or prophylaxis of a host infected    with Flaviviridae that includes the administration of an effective    amount of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, its pharmaceutically acceptable salt or    composition in combination and/or alternation with one or more    effective anti-HCV agent;-   (j) a method for the treatment and/or prophylaxis of a host infected    with Flaviviridae that includes the administration of an effective    amount of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, or its pharmaceutically acceptable salt or    composition with the parent of a different a 1′, 2′, 3′ or    4′-branched β-D or β-L nucleoside;-   (k) a method for the treatment and/or prophylaxis of a host infected    with Flaviviridae that includes the administration of an effective    amount of a 2′ and/or 3′-prodrug of a β-D-2′-methyl-cytidine, or its    pharmaceutically acceptable salt or composition thereof;-   (l) a method for the treatment and/or prophylaxis of a host infected    with Flaviviridae that includes the administration of an effective    amount of the 2′-valyl or acetyl ester of β-D-2′-methyl-cytidine, or    its pharmaceutically acceptable salt or composition thereof;-   (m) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, and pharmaceutically acceptable salts and    compositions thereof for the treatment and/or prophylaxis of a    Flaviviridae infection in a host;-   (n) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, its pharmaceutically acceptable salt or    composition in combination and/or alternation with one or more    effective anti-HCV agent for the treatment and/or prophylaxis of a    Flaviviridae infection in a host;-   (o) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, or its pharmaceutically acceptable salt or    composition with the parent of a different a 1′, 2′, 3′ or    4′-branched β-D or β-L nucleoside for the treatment and/or    prophylaxis of a Flaviviridae infection in a host;-   (p) use of a 2′ and/or 3′-prodrug of a β-D-2′-methyl-cytidine, or    its pharmaceutically acceptable salt or composition thereof for the    treatment and/or prophylaxis of a Flaviviridae infection in a host;-   (q) use of the 3′-valyl or acetyl ester of β-D-2′-methyl-cytidine,    or its pharmaceutically acceptable salt or composition thereof for    the treatment and/or prophylaxis of a Flaviviridae infection in a    host;-   (r) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, and pharmaceutically acceptable salts and    compositions thereof in the manufacture of a medicament for    treatment and/or prophylaxis of a Flaviviridae infection;-   (s) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, its pharmaceutically acceptable salt or    composition in combination and/or alternation with one or more    effective anti-HCV agent in the manufacture of a medicament for the    treatment and/or prophylaxis of a Flaviviridae infection in a host;-   (t) use of a 2′ and/or 3′-prodrug of a 1′, 2′, 3′ or 4′-branched β-D    or β-L nucleoside, or its pharmaceutically acceptable salt or    composition with the parent of a different a 1′, 2′, 3′ or    4′-branched β-D or β-L nucleoside in the manufacture of a medicament    for the treatment and/or prophylaxis of a Flaviviridae infection in    a host;-   (u) use of a 2′ and/or 3′-prodrug of a β-D-2′-methyl-cytidine, or    its pharmaceutically acceptable salt or composition thereof in the    manufacture of a medicament for the treatment and/or prophylaxis of    a Flaviviridae infection in a host; and-   (v) use of the 2′-valyl or acetyl ester of β-D-2′-methyl-cytidine,    or its pharmaceutically acceptable salt or composition thereof in    the manufacture of a medicament for the treatment and/or prophylaxis    of a Flaviviridae infection in a host.

Flaviviridae included within the scope of this invention are discussedgenerally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., andHowley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter31, 1996. In a particular embodiment of the invention, the Flaviviridaeis HCV. In an alternate embodiment of the invention, the Flaviviridae isa flavivirus or pestivirus. Specific flaviviruses include, withoutlimitation: Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui,Bussuquara, Cacipacore, Carey Island, Dakar bat, Dengue 1, Dengue 2,Dengue 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova,Hypr, llheus, Israel turkey meningoencephalitis, Japanese encephalitis,Jugra, Jutiapa, Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge,Kunjin, Kyasanur Forest disease, Langat, Louping ill, Meaban, Modoc,Montana myotis leukoencephalitis, Murray valley encephalitis, Naranjal,Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, Powassan, RioBravo, Rocio, Royal Farm, Russian spring-summer encephalitis, Saboya,St. Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, Sepik,Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, Uganda S, Usutu,Wesselsbron, West Nile, Yaounde, Yellow fever, and Zika.

Pestiviruses included within the scope of this invention are discussedgenerally in Fields Virology, Editors: Fields, B. N., Knipe, D. M., andHowley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., Chapter33, 1996. Specific pestiviruses include, without limitation: bovineviral diarrhea virus (“BVDV”), classical swine fever virus (“CSFV,” alsocalled hog cholera virus), and border disease virus (“BDV”).

I. Active Compounds

In a first principal embodiment, a compound of Formula (I), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R² and R³ are independently H, phosphate (including mono-, di- ortriphosphate and a stabilized phosphate); straight chained, branched orcyclic alkyl (including lower alkyl); acyl (including lower acyl);CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl,sulfonate ester including alkyl or arylalkyl sulfonyl includingmethanesulfonyl and benzyl, wherein the phenyl group is optionallysubstituted with one or more substituents as described in the definitionof aryl given herein; alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alipid, including a phospholipid; an amino acid; and amino acid residue,a carbohydrate; a peptide; cholesterol; or other pharmaceuticallyacceptable leaving group which when administered in vivo is capable ofproviding a compound wherein R¹, R² and/or R³ is independently H orphosphate (including mono-, di- or triphosphate); wherein in oneembodiment R² and/or R³ is not phosphate (including mono-, di- ortriphosphate or a stabilized phosphate prodrug);wherein at least one of R² and R³ is not hydrogen;Y¹ is hydrogen, bromo, chloro, fluoro, iodo, CN, OH, OR⁴, NH₂, NHR⁴,NR⁴R⁵, SH or SR⁴;X¹ is a straight chained, branched or cyclic optionally substitutedalkyl, CH₃, CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, CH₂OH, optionally substituted alkenyl, optionallysubstituted alkynyl, COOH, COOR⁴, COO-alkyl, COO-aryl, CO-Oalkoxyalkyl,CONH₂, CONHR⁴, CON(R⁴)₂, chloro, bromo, fluoro, iodo, CN, N₃, OH, OR⁴,NH₂, NHR⁴, NR⁴R⁵, SH or SR⁵;X² is H, straight chained, branched or cyclic optionally substitutedalkyl, CH₃, CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, CH₂OH, optionally substituted alkenyl, optionallysubstituted alkynyl, COOH, COOR⁴, COO-alkyl, COO-aryl, CO-Oalkoxyalkyl,CONH₂, CONHR⁴, CON(R⁴)₂, chloro, bromo, fluoro, iodo, CN, N₃, OH, OR⁴,NH₂, NHR⁴, NR⁴R⁵, SH or SR⁵; andwherein each Y³ is independently H, F, Cl, Br or I;each R⁴ and R⁵ is independently hydrogen, acyl (including lower acyl),alkyl (including but not limited to methyl, ethyl, propyl andcyclopropyl), lower alkyl, alkenyl, alkynyl or cycloalkyl.

In a preferred subembodiment, a compound of Formula (I) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (I)or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:

R¹ is H or phosphate (preferably H);R² and R³ are independently H, phosphate, acyl or an amino acid residue,wherein at least one of R² and R³ is acyl or an amino acid residue;X¹ is CH₃, CF₃ or CH₂CH₃;X² is H or NH₂; andY is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a second principal embodiment, a compound of Formula (II) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (I):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R², R³, R⁴, R⁵, Y¹, Y³, X¹ and X² are as defined above.

In a preferred subembodiment, a compound of Formula (II), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (II)or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:

R¹ is H or phosphate (preferably H);R² and R³ are independently H, phosphate, acyl or an amino acid residue,wherein at least one of R² and R³ is acyl or an amino acid residue;X¹ is CH₃, CF₃ or CH₂CH₃;X² is H, F, Cl, Br, I or CH₃; andY is hydrogen, bromo, chloro, fluoro, iodo, NH₂ or OH.

In a third principal embodiment, a compound of Formula (III), (IV) or(V) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (III), (IV), or (V):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R², R³, R⁴, R⁵, Y, Y¹ and X² are as defined above;Base is selected from the group consisting of:

each W¹, W², W³ and W⁴ is independently N, CH, CF, CI, CBr, CCl, CCN,CCH₃, CCF₃, CCH₂CH₃, CC(O)NH₂, CC(O)NHR⁴, CC(O)N(R⁴)₂, CC(O)OH, CC(O)OR⁴or CX³;each W* is independently O, S, NH or NR⁴;wherein for Base (B), W⁴ cannot be CH if W¹, W² and W³ are N;wherein for Base (E), (F), (K), (L), (W) and (X), W⁴ cannot be CH if W¹is N;X is O, S, S, SO₂, CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ orC(R⁴)₂;X* is CH, CF, CY³ or CR⁴;each X³ is independently a straight chained, branched or cyclicoptionally substituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃,CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (includinghalogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃,CF₂CF₃, C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl,Br-vinyl, optionally substituted alkynyl, haloalkynyl, N₃, CN, —C(O)OH,—C(O)OR⁴, —C(O)O(lower alkyl), —C(O)NH₂, —C(O)NHR⁴, —C(O)NH(loweralkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂, OH, OR⁴, —O(acyl), —O(loweracyl), —O(alkyl), —O(lower alkyl), —O(alkenyl), —O(alkynyl),—O(aralkyl), —O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R⁴), —S(loweralkyl), —S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), chloro,bromo, fluoro, iodo, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵, —NH(acyl),—N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂;each Y² is independently O, S, NH or NR⁴;each Y³ is independently H, F, Cl, Br or I;each R⁶ is independently an optionally substituted alkyl (includinglower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH,halogenated alkyl (including halogenated lower alkyl), CF₃, C(Y³)₃,2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, optionallysubstituted alkenyl, haloalkenyl, Br-vinyl, optionally substitutedalkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl),—CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂,—CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴,—(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴,—(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂ or cyano;each R⁷ is independently OH, OR², optionally substituted alkyl(including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);alternatively, R⁶ and R⁷ can come together to form a spiro compoundselected from the group consisting of optionally substituted carbocycle(preferably a 3-7 membered carbocyclic ring) or optionally substitutedheterocycle (preferably a 3-7 membered heterocyclic ring having one ormore O, S and/or N); andeach m is independently 0, 1 or 2.

In a first subembodiment, the compound of Formula (III), (IV) or (V), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, or the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (III), (IV), or (V) ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, wherein:

R¹ is H or phosphate (preferably H);R² and R³ are independently H, phosphate, acyl or an amino acid residue,wherein at least one of R² and R³ is acyl or an amino acid residue;W⁴ is CX³;X³ is CH₃, CF₃ or CH₂CH₃;R⁶ is alkyl; andX is O, S, SO₂ or CH₂.

In a second subembodiment, the compound of Formula (III), (IV) or (V),or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, or the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (III), (IV) or (V), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, wherein:

R¹ is H or phosphate (preferably H);R² and R³ are independently H, phosphate, acyl or an amino acid residue,wherein at least one of R² and R³ is an amino acid residue;W⁴ is CX³;X³ is CH₃, CF₃ or CH₂CH₃;R⁶ is alkyl; andX is O, S, S, SO₂ or CH₂.

In a third subembodiment, the compound of Formula (III), (IV) or (V), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, or the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (III), (IV) or (V), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, wherein:

R¹ is H or phosphate (preferably H);R² and R³ are independently H, phosphate, acyl or an amino acid residue,wherein at least one of R² and R³ is acyl or an amino acid residue;W⁴ is CX³;X³ is CH₃, CF₃ or CH₂CH₃;R⁶ is alkyl; and

X is O.

In even more preferred subembodiment, the compound of Formula (IV(a)),or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as themethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (IV(a)):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:Base is as defined herein; optionally substituted with an amine orcyclopropyl (e.g., 2-amino, 2,6-diamino or cyclopropyl guanosine);R⁷ is halo (F, Cl, Br or I), though preferably F;R¹ is H; phosphate (including monophosphate, diphosphate, triphosphate,or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl(including lower alkyl); sulfonate ester including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl groupis optionally substituted with one or more substituents as described inthe definition of aryl given herein; a lipid, including a phospholipid;an amino acid; a carbohydrate; a peptide; cholesterol; or otherpharmaceutically acceptable leaving group which when administered invivo is capable of providing a compound wherein R¹ or R² isindependently H or phosphate. In one embodiment R² is not phosphate(including monophosphate, diphosphate, triphosphate, or a stabilizedphosphate prodrug); andR² is phosphate (including monophosphate, diphosphate, triphosphate, ora stabilized phosphate prodrug); acyl (including lower acyl); alkyl(including lower alkyl); sulfonate ester including alkyl or arylalkylsulfonyl including methanesulfonyl and benzyl, wherein the phenyl groupis optionally substituted with one or more substituents as described inthe definition of aryl given herein; a lipid, including a phospholipid;an amino acid; a carbohydrate; a peptide; cholesterol; or otherpharmaceutically acceptable leaving group which when administered invivo is capable of providing a compound wherein R¹ or R² isindependently H or phosphate. In one embodiment R² is not phosphate(including monophosphate, diphosphate, triphosphate, or a stabilizedphosphate prodrug).

In a fourth principal embodiment, a compound of Formula (VI) or (VII) ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (VI)or (VII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, wherein:Base, R, R¹, R⁴, R⁵, R⁶, R⁷, Y, Y¹, Y², Y³, W*, W¹, W², W³, W⁴, X, X*,X¹, X², and X³ are as defined above;wherein, in one embodiment, R⁸ in Formula (VI) is —OH or —NH₂ only whenX is carbon; andwherein;each R⁸ and R¹¹ is independently hydrogen, an optionally substitutedalkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(loweralkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH,—(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂,—(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂, cyano, NH-acyl or N(acyl)₂;each R⁹ and R¹⁰ are independently hydrogen, OH, OR², optionallysubstituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenatedlower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);each m is independently 0, 1 or 2; andalternatively, R⁶ and R¹⁰, R⁷ and R⁹, R⁸ and R⁷ or R⁹ and R¹¹ can cometogether to form a bridged compound selected from the group consistingof optionally substituted carbocycle (preferably a 3-7 memberedcarbocyclic ring) or optionally substituted heterocycle (preferably a3-7 membered heterocyclic ring having one or more O, S and/or N); oralternatively, R⁶ and R⁷ or R⁹ and R¹⁰ can come together to form a spirocompound selected from the group consisting of optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring) or optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N).

In a particularly preferred embodiment, a compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (VI)or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, in which:

-   -   X is O, S, SO or SO₂; and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CHF, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂),OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a particularly preferred alternative embodiment, a compound ofFormula (VI), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (VI) or a pharmaceutically acceptable salt orprodrug, or a stereoisomeric, tautomeric or polymorphic form thereof; inwhich:

-   -   X is O, S, SO or SO₂; and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VI), or its pharmaceutically acceptable salt or prodrug thereof, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (VI) or a pharmaceutically acceptable salt orprodrug, or a stereoisomeric, tautomeric or polymorphic form thereof, isprovided, in which:

-   -   X is O, S, SO or SO₂; and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —Cl, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ is independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VI), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VI) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X is O, S, SO or SO₂; and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a particularly preferred embodiment, a compound of Formula (VI), orits pharmaceutically acceptable salt or prodrug thereof, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VI) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X is CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ or C(R⁴)₂;        and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a particularly preferred alternative embodiment, a compound ofFormula (VI), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which:

-   -   X is CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ or C(R⁴)₂;        and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂CO₂R₄, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R′″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VI), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VI) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X is CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ or C(R⁴)₂;        and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO. NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VI), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VI) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X is CH₂, CH₂OH, CHF, CF₂, C(Y³)₂, CHCN, C(CN)₂, CHR⁴ or C(R⁴)₂;        and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a particularly preferred embodiment, a compound of Formula (VII), orits pharmaceutically acceptable salt or prodrug thereof, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VII) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X* is CH, CF, CY³ or CR⁴; and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R₄, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂COR⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   wherein R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a particularly preferred alternative embodiment, a compound ofFormula (VII), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VII) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X* is CH, CF, CY³ or CR⁴; and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁹ is independently hydrogen, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —OH, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   each R¹⁰ is independently hydrogen, an optionally substituted        lower alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted cycloalkyl, CH₂OH,        CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃,        CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VII), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X* is CH, CF, CY³ or CR⁴; and/or    -   each R⁶ is independently an optionally substituted lower alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃,        CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, or (CH₂)_(m)CONHR⁴; and/or    -   each R⁷ is independently —OH, optionally substituted lower        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, optionally substituted cycloalkyl, —O-alkyl,        —O-alkenyl, —O-alkynyl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F,        Cl, Br, I, CN, NC, SCN, OCN, NCO, NO₂, NH₂, N₃, NH-acyl,        NH-alkyl, N-dialkyl, NH-alkenyl, NH-alkynyl, NH-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-alkenyl, S-alkynyl, S-aralkyl,        S-acyl, S-cycloalkyl, CO₂-alkyl, CONH-alkyl, CON-dialkyl,        CONH-alkenyl, CONH-alkynyl, CONH-aralkyl, CONH-cycloalkyl,        CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN,        CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R⁴, (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴,        (CH₂)_(m)CONH₂, (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴, an        optionally substituted 3-7 membered carbocyclic, and an        optionally substituted 3-7 membered heterocyclic ring having O,        S and/or N independently as a heteroatom taken alone or in        combination; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In another particularly preferred embodiment, a compound of Formula(VII), or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (VII) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, inwhich:

-   -   X* is CH, CF, CY³ or CR⁴; and/or    -   R⁶ and R⁷ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   R⁹ and R¹⁰ come together to form a spiro compound selected from        the group consisting of optionally substituted 3-7 membered        spiro carbocyclic or heterocyclic compound having one or more N,        O and/or S atoms, said heteroatoms independently taken alone or        in combination with one another; and/or    -   each R⁸ and R¹¹ is independently H, CH₃, CH₂OH, CH₂F, CH₂N₃,        (CH₂)_(m)COOH, (CH₂)_(m)COOR⁴, (CH₂)_(m)CONH₂,        (CH₂)_(m)CON(R⁴)₂, (CH₂)_(m)CONHR⁴ and N-acyl; and/or    -   each m is independently 0 or 1; and/or    -   Base is selected from one of the following:

-   -   -   wherein:        -   each R′, R″, R′″ and R″″ is independently selected from the            group consisting of H, OH, substituted or unsubstituted            alkyl, substituted or unsubstituted alkenyl, substituted or            unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,            O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl,            O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl,            N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,            S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂,            CO₂-alkyl, CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH,            (CH₂)_(m)OH, (CH₂)_(m)NH₂, (CH₂)_(m)COOH, (CH₂)_(m)CN,            (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;        -   W is C—R″ or N;        -   T and V independently are CH or N;        -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or            N;        -   Q₁ and Q₂ independently are N or C—R;        -   R is H, alkyl or acyl;        -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and        -   tautomeric forms thereof.

In a first subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vive is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ are independently OR²,alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine, iodine,NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁸ and R¹⁰ areindependently H, alkyl (including lower alkyl), chlorine, bromine, oriodine; (5) X is O, S, SO₂ or CH₂; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃or CH₂CH₃.

In a second subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy,O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂, amino,loweralkylamino, or di(loweralkyl)amino; (3) R⁷ and R⁹ are independentlyOR²; (4) R⁸ and R¹⁰ are independently H, alkyl (including lower alkyl),chlorine, bromine, or iodine; (5) X is O, S, SO₂ or CH₂; (6) W⁴ is CX³;and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a third subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein: a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vive is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy,O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂, amino,loweralkylamino or di(loweralkyl)amino; (3) R⁷ and R⁹ are independentlyOR², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (4) R⁸ andR¹⁰ are H; (5) X is O, S, SO₂ or CH₂; (6) W⁴ is CX³; and (7) X³ is CH₃,CF₃ or CH₂CH₃.

In a fourth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl, alkenyl, alkynyl, Br-vinyl, hydroxy,O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂, amino,loweralkylamino, or di(loweralkyl)amino; (3) R⁷ and R⁹ are independentlyOR², alkyl, alkenyl, alkynyl, Br-vinyl, O-alkenyl, chlorine, bromine,iodine, NO₂, amino, loweralkylamino, or di(loweralkyl)amino; (4) R⁸ andR¹⁰ are independently H, alkyl (including lower alkyl), chlorine,bromine, or iodine; (5) X is O; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ orCH₂CH₃.

In a fifth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ are independently OR¹; (4)R⁸ and R¹⁰ are independently H, alkyl (including lower alkyl), chlorine,bromine or iodine; (5) X is O, S, SO₂ or CH₂; (6) W⁴ is CX³; and (7) X³is CH₃, CF₃ or CH₂CH₃.

In a sixth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ are independently OR²,alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl,chlorine, bromine, iodine, NO₂, amino, loweralkylamino, ordi(loweralkyl)-amino; (4) R⁸ and R¹⁰ are H; (5) X is O, S, SO₂, or CH₂;(6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a seventh subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ are independently OR²,alkyl (including lower alkyl), alkenyl, alkynyl, Br-vinyl, O-alkenyl,chlorine, bromine, iodine, NO₂, amino, loweralkylamino ordi(loweralkyl)-amino; (4) R⁸ and R¹⁰ are independently H, alkyl(including lower alkyl), chlorine, bromine or iodine; (5) X is O; (6) W⁴is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a eighth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino or di(loweralkyl)amino; (3) R⁷ and R⁹ areindependently OR²; (4) R⁸ and R¹⁰ are hydrogen; (6) X is O, S, SO₂ orCH₂; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a ninth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino or di(loweralkyl)amino; (3) R⁷ and R⁹ areindependently OR²; (4) R⁸ and R¹⁰ are independently H, alkyl (includinglower alkyl), chlorine, bromine or iodine; (5) X is O; (6) W⁴ is CX³;and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a tenth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate (including monophosphate, diphosphate,triphosphate, or a stabilized phosphate prodrug); acyl (including loweracyl); alkyl (including lower alkyl); sulfonate ester including alkyl orarylalkyl sulfonyl including methanesulfonyl and benzyl, wherein thephenyl group is optionally substituted with one or more substituents asdescribed in the definition of aryl given herein; a lipid, including aphospholipid; an amino acid; a carbohydrate; a peptide; cholesterol; orother pharmaceutically acceptable leaving group which when administeredin vivo is capable of providing a compound wherein R¹ is independently Hor phosphate; (2) R⁶ is alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo, fluoro, iodo, NO₂,amino, loweralkylamino or di(loweralkyl)amino; (3) R⁷ and R⁹ areindependently OR², alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino, or di(loweralkyl)amino; (4) R⁸ and R¹⁰ are hydrogen;(5) X is O; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In an eleventh subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate; (2) R⁶ is alkyl (including lower alkyl),alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkyl, O-alkenyl, chloro, bromo,fluoro, iodo, NO₂, amino, loweralkylamino or di(loweralkyl)amino; (3) R⁷and R⁹ are independently OR²; (4) R⁸ and R¹⁰ are hydrogen; (5) X is O,S, SO₂ or CH₂; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a twelfth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ areindependently OR²; (4) R⁸ and R¹⁰ are hydrogen; (5) X is O, S, SO₂, orCH₂; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a thirteenth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ areindependently OR²; (4) R⁸ and R¹⁰ are independently H, alkyl (includinglower alkyl), chlorine, bromine, or iodine; (5) X is O; (6) W⁴ is CX³;and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In a fourteenth subembodiment, the compound of Formula (VI), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which: (1) R¹ isindependently H or phosphate; (2) R⁶ is alkyl; (3) R⁷ and R⁹ areindependently OR², alkyl (including lower alkyl), alkenyl, alkynyl,Br-vinyl, O-alkenyl, chlorine, bromine, iodine, NO₂, amino,loweralkylamino or di(loweralkyl)amino; (4) R⁸ and R¹⁰ are hydrogen; (5)X is O; (6) W⁴ is CX³; and (7) X³ is CH₃, CF₃ or CH₂CH₃.

In even more preferred subembodiments, the compound of Formula (VI), ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, and the method for the treatmentof a host infected with a Flaviviridae comprising administering aneffective treatment amount of compound of Formula (VI) or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, in which:

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methylguanine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 6-methylcytosine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 6-methylthymidine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 6-methyluracil; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4) R⁷and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methyladenine; (2) R¹ is phosphate; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is ethyl; (4) R⁷and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is propyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is butyl; (4) R⁷and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is O;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ is hydrogen and R⁹ is hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6)X is O;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is S;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is SO₂;

(1) Base is 8-methyladenine; (2) R¹ is hydrogen; (3) R⁶ is methyl; (4)R⁷ and R⁹ are hydroxyl; (5) R⁸ and R¹⁰ are hydrogen; and (6) X is CH₂.

In a fifth principal embodiment, a compound of Formula (VIII), (IX) or(X) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric, or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (VIII), (IX), or (X):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R¹, R², R³, R⁴, R⁵, Y³, X, and X* are as defined above;Base* is a purine or pyrimidine base as defined herein;each R¹² is independently a substituted alkyl (including lower alkyl),CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl(including halogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F,CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, substituted alkenyl, haloalkenyl(but not Br-vinyl), substituted alkynyl, haloalkynyl, —CH₂C(O)OH,—CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂;each R¹³ is independently substituted alkyl (including lower alkyl),CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl(including halogenated lower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F,CH₂Cl, CH₂CF₃, CF₂CF₃, C(Y³)₂C(Y³)₃, substituted alkenyl, haloalkenyl(but not Br-vinyl), substituted alkynyl, haloalkynyl, optionallysubstituted carbocycle (preferably a 3-7 membered carbocyclic ring),optionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N), optionallysubstituted heteroaryl (preferably a 3-7 membered heteroaromatic ringhaving one or more O, S and/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)SH, —CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl),—CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂,—CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴,—(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴,—(CH₂)_(m)C(O)S(lower alkyl), —(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴,—(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)SH, —C(O)SR⁴,—C(O)S(lower alkyl), —C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl),—C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂, —O(R⁴), —O(alkynyl), —O(aralkyl),—O(cycloalkyl), —S(acyl), —S(lower acyl), —S(R⁴), —S(lower alkyl),—S(alkenyl), —S(alkynyl), —S(aralkyl), —S(cycloalkyl), —NHR⁴, —NR⁴R⁵,—NH(alkenyl), —NH(alkynyl), —NH(aralkyl), —NH(cycloalkyl), SCN, OCN, NCOor fluoro;alternatively, R¹² and R¹³ can come together to form a spiro compoundselected from the group consisting of optionally substituted carbocycle(preferably a 3-7 membered carbocyclic ring) or optionally substitutedheterocycle (preferably a 3-7 membered heterocyclic ring having one ormore O, S and/or N); andeach m is independently 0, 1 or 2.

In a sixth principal embodiment, a compound of Formula (XI) or (XII) ora pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric, or polymorphic form thereof, is provided, as well as amethod for the treatment of a host infected with a Flaviviridaecomprising administering an effective treatment amount of compound ofFormula (XI) or (XII):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:Base*, R, R¹, R², R³, R⁴, R⁵, R¹², R¹³, Y, Y¹, Y², Y³, W*, W¹, W², W³,W⁴, X, X*, X² and X³ are as defined above;wherein, in one embodiment, R⁸ in Formula (XI) is —OH or —NH₂ only whenX is carbon; and wherein;each R⁸ and R¹¹ is independently hydrogen, an optionally substitutedalkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenated loweralkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, —CH₂C(O)OH, —CH₂C(O)OR⁴,—CH₂C(O)O(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴, —CH₂C(O)NH(loweralkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂, —(CH₂)_(m)C(O)OH,—(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl), —(CH₂)_(m)C(O)NH₂,—(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl), —(CH₂)_(m)C(O)N(R⁴)₂,—(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴, —C(O)O(lower alkyl),—C(O)NH₂, —C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(loweralkyl)₂, cyano, NH-acyl or N(acyl)₂;each R⁹ and R¹⁰ are independently hydrogen, OH, OR², optionallysubstituted alkyl (including lower alkyl), CH₃, CH₂CN, CH₂N₃, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, CH₂OH, halogenated alkyl (including halogenatedlower alkyl), CF₃, C(Y³)₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, CF₂CF₃,C(Y³)₂C(Y³)₃, optionally substituted alkenyl, haloalkenyl, Br-vinyl,optionally substituted alkynyl, haloalkynyl, optionally substitutedcarbocycle (preferably a 3-7 membered carbocyclic ring), optionallysubstituted heterocycle (preferably a 3-7 membered heterocyclic ringhaving one or more O, S and/or N), optionally substituted heteroaryl(preferably a 3-7 membered heteroaromatic ring having one or more O, Sand/or N), —CH₂C(O)OH, —CH₂C(O)OR⁴, —CH₂C(O)O(lower alkyl), —CH₂C(O)SH,—CH₂C(O)SR⁴, —CH₂C(O)S(lower alkyl), —CH₂C(O)NH₂, —CH₂C(O)NHR⁴,—CH₂C(O)NH(lower alkyl), —CH₂C(O)N(R⁴)₂, —CH₂C(O)N(lower alkyl)₂,—(CH₂)_(m)C(O)OH, —(CH₂)_(m)C(O)OR⁴, —(CH₂)_(m)C(O)O(lower alkyl),—(CH₂)_(m)C(O)SH, —(CH₂)_(m)C(O)SR⁴, —(CH₂)_(m)C(O)S(lower alkyl),—(CH₂)_(m)C(O)NH₂, —(CH₂)_(m)C(O)NHR⁴, —(CH₂)_(m)C(O)NH(lower alkyl),—(CH₂)_(m)C(O)N(R⁴)₂, —(CH₂)_(m)C(O)N(lower alkyl)₂, —C(O)OH, —C(O)OR⁴,—C(O)O(lower alkyl), —C(O)SH, —C(O)SR⁴, —C(O)S(lower alkyl), —C(O)NH₂,—C(O)NHR⁴, —C(O)NH(lower alkyl), —C(O)N(R⁴)₂, —C(O)N(lower alkyl)₂,—O(acyl), —O(lower acyl), —O(R⁴), —O(alkyl), —O(lower alkyl),—O(alkenyl), —O(alkynyl), —O(aralkyl), —O(cycloalkyl), —S(acyl),—S(lower acyl), —S(R⁴), —S(lower alkyl), —S(alkenyl), —S(alkynyl),—S(aralkyl), —S(cycloalkyl), NO₂, NH₂, —NH(lower alkyl), —NHR⁴, —NR⁴R⁵,—NH(acyl), —N(lower alkyl)₂, —NH(alkenyl), —NH(alkynyl), —NH(aralkyl),—NH(cycloalkyl), —N(acyl)₂, azido, cyano, SCN, OCN, NCO or halo (fluoro,chloro, bromo, iodo);each m is independently 0, 1 or 2; andalternatively, R⁸ and R¹³, R⁹ and R¹³, R⁹ and R¹¹ or R¹⁰ and R¹² cancome together to form a bridged compound selected from the groupconsisting of optionally substituted carbocycle (preferably a 3-7membered carbocyclic ring) or optionally substituted heterocycle(preferably a 3-7 membered heterocyclic ring having one or more O, Sand/or N); oralternatively, R¹² and R¹³ or R⁹ and R¹⁰ can come together to form aspiro compound selected from the group consisting of optionallysubstituted carbocycle (preferably a 3-7 membered carbocyclic ring) oroptionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N).

In a particular aspect of the invention, compounds of the Formula (XIII)or (XIV) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (XIII) or (XIV):

or a pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:R₃ is selected from the group consisting of H; mono-, di-, andtri-phosphate or a stabilized phosphate prodrug; acyl; a sulfonateester; optionally substituted alkyl sulfonyl; optionally substitutedarylsulfonyl; a lipid; an amino acid; a carbohydrate; a peptide;cholesterol; and a pharmaceutically acceptable leaving group which whenadministered in vivo is capable of providing a compound wherein R₃ isindependently H, or mono-, di- or triphosphate;X″ is selected from the group consisting of one or more O, S, SO, SO₂,N, NH, NR and CH₂ wherein any of the aforementioned may be optionallysubstituted and may be variably positioned so as to form a 3-7 memberedring;R is H, alkyl or acyl;B indicates a spiro compound selected from the group consisting ofoptionally substituted carbocycle (preferably a 3-7 membered carbocyclicring) or optionally substituted heterocycle (preferably a 3-7 memberedheterocyclic ring having one or more O, S and/or N); andBase is selected from the group consisting of:

-   -   wherein:    -   each R′, R″, R′″ and R″″ are independently selected from the        group consisting of H, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,        O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, O-cycloalkyl,        NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl,        S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂, CO₂-alkyl, CONH-alkyl,        CON-dialkyl, OH, CF₃, CH₂OH, (CH₂)_(m)OH, (CH₂)_(m)NH₂,        (CH₂)_(m)COOH, (CH₂)_(m)CN, (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;    -   m is 0 or 1;    -   W is C—R″ or N;    -   T and V independently are CH or N;    -   Q is CH, —CCl, —CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or N;    -   Q₁ and Q₂ independently are N or C—R;    -   R is H, alkyl or acyl;    -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH; and    -   tautomeric forms thereof.

In a second particular aspect of the invention, a compound of Formula(XV), (XVI) or (XVII) or a pharmaceutically acceptable salt or prodrug,or a stereoisomeric, tautomeric or polymorphic form thereof, isprovided, as well as a method for the treatment of a host infected witha Flaviviridae comprising administering an effective treatment amount ofcompound of Formula (XV), (XVI), or (XVII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:G and E independently are selected from the group consisting of H, CH₃,CH₂OH, CH₂F, CH₂N₃, CH₂CN, (CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CONH₂,(CH₂)_(m)CONR₂, (CH₂)_(m)CONHR and N-acyl;R is H, alkyl or acyl;m is 0 or 1; andR³ and Base are as defined for Formula (XIII).

Alternatively, for compound of Formula (XVII), at most one of G and Ecan further be hydrogen.

In a third particular aspect of the invention, a compound of Formula(XVIII) or a pharmaceutically acceptable salt or prodrug, or astereoisomeric, tautomeric or polymorphic form thereof, is provided, aswell as a method for the treatment of a host infected with aFlaviviridae comprising administering an effective treatment amount ofcompound of Formula (XVIII):

or its pharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:M is selected from the group consisting of S, SO, and SO₂; andR₃ and Base are as defined for Formula (XIII).

In a fourth particular aspect of the invention, a compound of Formula(XIX), (XX), (XXI) (XXII) or (XXIII) or a pharmaceutically acceptablesalt or prodrug, or a stereoisomeric, tautomeric or polymorphic formthereof, is provided, as well as a method for the treatment of a hostinfected with a Flaviviridae comprising administering an effectivetreatment amount of compound of Formula (XIX), (XXI), (XXII), or(XXIII):

or its pharmaceutically acceptable salt or prodrug or a stereoisomeric,tautomeric or polymorphic form thereof, wherein:A is selected from the group consisting of optionally substituted loweralkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R,(CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CO—NH₂, (CH₂)_(m)CONR₂, and(CH₂)_(m)CONHR;Y is selected from the group consisting of H, optionally substitutedlower alkyl, cycloalkyl, alkenyl, alkynyl, CH₂OH, CH₂NH₂, CH₂NHCH₃,CH₂N(CH₃)₂, CH₂F, CH₂Cl, CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R,(CH₂)_(m)COOH, (CH₂)_(m)COOR, (CH₂)_(m)CONH₂, (CH₂)_(m)CONR₂, and(CH₂)_(m)CONHR;R is H, alkyl or acyl;X is selected from the group consisting of —OH, optionally substitutedalkyl, cycloalkyl, alkenyl, alkynyl, —O-alkyl, —O-alkenyl, —O-alkynyl,—O-aryl, —O-aralkyl, —O-cycloalkyl-, O-acyl, F, Cl, Br, I, CN, NC, SCN,OCN, NCO, NO₂, NH₂, N₃, NH-acyl, NH-alkyl, N-dialkyl, NH-alkenyl,NH-alkynyl, NH-aryl, NH-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-alkenyl,S-alkynyl, S-aryl, S-aralkyl, S-acyl, S-cycloalkyl, CO₂-alkyl,CONH-alkyl, CON-dialkyl, CONH-alkenyl, CONH-alkynyl, CONH-aralkyl,CONH-cycloalkyl, CH₂OH, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, CH₂F, CH₂Cl,CH₂N₃, CH₂CN, CH₂CF₃, CF₃, CF₂CF₃, CH₂CO₂R, (CH₂)_(m)COOH,(CH₂)_(m)COOR, (CH₂)_(m)CONH₂, (CH₂)_(m)CONR₂, (CH₂)_(m)CONHR, anoptionally substituted 3-7 membered carbocyclic, and an optionallysubstituted 3-7 membered heterocyclic ring having O, S and/or Nindependently as a heteroatom taken alone or in combination;m is 0 or 1;R₃ is selected from the group consisting of H; mono-, di-, andtri-phosphate or a stabilized phosphate prodrug; substituted orunsubstituted alkyl; acyl; a sulfonate ester; optionally substitutedalkyl sulfonyl; optionally substituted arylsulfonyl; a lipid; an aminoacid; a carbohydrate; a peptide; cholesterol; and a pharmaceuticallyacceptable leaving group which when administered in vivo is capable ofproviding a compound wherein R₁ is independently H, or mono-, di- ortriphosphate; and Base is a non-natural base selected from the group of:

-   -   wherein:    -   each R′, R″, R′″ and R″″ is independently selected from the        group consisting of H, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, cycloalkyl, Br-vinyl, —O-alkyl,        O-alkenyl, O-alkynyl, O-aryl, O-aralkyl, —O-acyl, O-cycloalkyl,        NH₂, NH-alkyl, N-dialkyl, NH-acyl, N-aryl, N-aralkyl,        NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl, S-cycloalkyl,        S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂, CO₂-alkyl, CONH-alkyl,        CON-dialkyl, OH, CF₃, CH₂OH, (CH₂)_(m)OH, (CH₂)_(m)NH₂,        (CH₂)_(m)COOH, (CH₂)_(m)CN, (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂;    -   m is 0 or 1;    -   W is C—R″ or N;    -   T and V independently are CH or N;    -   Q is CH, —CCl, —CBr, —CF, —Cl, —CCN, —C—COOH, —C—CONH₂, or N;    -   Q₁ and Q₂ independently are N or C—R″″; and    -   Q₃, Q₄, Q₅ and Q₆ independently are N or CH;    -   with the proviso that in bases (g) and (i), R′, R″″ are not H,        OH, or NH₂; and Q, T, V, Q₂, Q₅ and Q₆ are not N.

In another preferred embodiment, a compound of Formula (IX), or apharmaceutically acceptable salt or prodrug, or a stereoisomeric,tautomeric or polymorphic form thereof, is provided, as well as a methodfor the treatment of a host infected with a Flaviviridae comprisingadministering an effective treatment amount of compound of Formula (IX):

or a stereoisomeric, tautomeric or polymorphic form thereof, or apharmaceutically acceptable salt thereof, wherein:

R¹, R² and R³ are independently H; phosphate; straight chained, branchedor cyclic alkyl; acyl; CO-alkyl; CO-aryl; CO-alkoxyalkyl;CO-aryloxyalkyl; CO-substituted aryl; sulfonate ester; benzyl, whereinthe phenyl group is optionally substituted with one or moresubstituents; alkylsulfonyl; arylsulfonyl; aralkylsulfonyl; a lipid; anamino acid; a carbohydrate; a peptide; cholesterol; or apharmaceutically acceptable leaving group which when administered invivo is capable of providing a compound wherein R¹, R² and/or R³ isindependently H or phosphate;

X is O, S, SO₂ or CH₂;

Base* is a purine or pyrimidine base;

R¹² is C(Y³)₃;

Y³ is independently H, F, Cl, Br or I; and

R¹³ is fluoro.

In one subembodiment X is O, and Y³ is H. In another subembodiment, whenX is O and Y³ is H, R¹, R² and R³ are also H.

II. Stereochemistry

It is appreciated that nucleosides of the present invention have severalchiral centers and may exist in and be isolated in optically active andracemic forms. Some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any racemic,optically-active, diastereomeric, polymorphic, or stereoisomeric form,or mixtures thereof, of a compound of the invention, which possess theuseful properties described herein. It being well known in the art howto prepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase).

In particular, since the 1′ and 4′ carbons of the nucleoside are chiral,their nonhydrogen substituents (the base and the CHOR groups,respectively) can be either cis (on the same side) or trans (on oppositesides) with respect to the sugar ring system. The four optical isomerstherefore are represented by the following configurations (whenorienting the sugar moiety in a horizontal plane such that the oxygenatom is in the back): cis (with both groups “up”, which corresponds tothe configuration of naturally occurring ß-D nucleosides), cis (withboth groups “down”, which is a nonnaturally occurring ß-Lconfiguration), trans (with the C2′ substituent “up” and the C4′substituent “down”), and trans (with the C2′ substituent “down” and theC4′ substituent “up”). The “D-nucleosides” are cis nucleosides in anatural configuration and the “L-nucleosides” are cis nucleosides in thenonnaturally occurring configuration.

Likewise, most amino acids are chiral (designated as L or D, wherein theL enantiomer is the naturally occurring configuration) and can exist asseparate enantiomers.

Examples of methods to obtain optically active materials are known inthe art, and include at least the following.

-   i) physical separation of crystals—a technique whereby macroscopic    crystals of the individual enantiomers are manually separated. This    technique can be used if crystals of the separate enantiomers exist,    i.e., the material is a conglomerate, and the crystals are visually    distinct;-   ii) simultaneous crystallization—a technique whereby the individual    enantiomers are separately crystallized from a solution of the    racemate, possible only if the latter is a conglomerate in the solid    state;-   iii) enzymatic resolutions—a technique whereby partial or complete    separation of a racemate by virtue of differing rates of reaction    for the enantiomers with an enzyme;-   iv) enzymatic asymmetric synthesis—a synthetic technique whereby at    least one step of the synthesis uses an enzymatic reaction to obtain    an enantiomerically pure or enriched synthetic precursor of the    desired enantiomer;-   v) chemical asymmetric synthesis—a synthetic technique whereby the    desired enantiomer is synthesized from an achiral precursor under    conditions that produce asymmetry (i.e., chirality) in the product,    which may be achieved using chiral catalysts or chiral auxiliaries;-   vi) diastereomer separations—a technique whereby a racemic compound    is reacted with an enantiomerically pure reagent (the chiral    auxiliary) that converts the individual enantiomers to    diastereomers. The resulting diastereomers are then separated by    chromatography or crystallization by virtue of their now more    distinct structural differences and the chiral auxiliary later    removed to obtain the desired enantiomer;-   vii) first- and second-order asymmetric transformations—a technique    whereby diastereomers from the racemate equilibrate to yield a    preponderance in solution of the diastereomer from the desired    enantiomer or where preferential crystallization of the diastereomer    from the desired enantiomer perturbs the equilibrium such that    eventually in principle all the material is converted to the    crystalline diastereomer from the desired enantiomer. The desired    enantiomer is then released from the diastereomer,-   viii) kinetic resolutions—this technique refers to the achievement    of partial or complete resolution of a racemate (or of a further    resolution of a partially resolved compound) by virtue of unequal    reaction rates of the enantiomers with a chiral, non-racemic reagent    or catalyst under kinetic conditions;-   ix) enantiospecific synthesis from non-racemic precursors—a    synthetic technique whereby the desired enantiomer is obtained from    non-chiral starting materials and where the stereochemical integrity    is not or is only minimally compromised over the course of the    synthesis;-   x) chiral liquid chromatography—a technique whereby the enantiomers    of a racemate are separated in a liquid mobile phase by virtue of    their differing interactions with a stationary phase. The stationary    phase can be made of chiral material or the mobile phase can contain    an additional chiral material to provoke the differing interactions;-   xi) chiral gas chromatography—a technique whereby the racemate is    volatilized and enantiomers are separated by virtue of their    differing interactions in the gaseous mobile phase with a column    containing a fixed non-racemic chiral adsorbent phase;-   xii) extraction with chiral solvents—a technique whereby the    enantiomers are separated by virtue of preferential dissolution of    one enantiomer into a particular chiral solvent;-   xiii) transport across chiral membranes—a technique whereby a    racemate is placed in contact with a thin membrane barrier. The    barrier typically separates two miscible fluids, one containing the    racemate, and a driving force such as concentration or pressure    differential causes preferential transport across the membrane    barrier. Separation occurs as a result of the non-racemic chiral    nature of the membrane which allows only one enantiomer of the    racemate to pass through.

III. Definitions

The term “alkyl”, as used herein, unless otherwise specified, refers toa saturated straight, branched, or cyclic, primary, secondary, ortertiary hydrocarbon of typically C₁ to C₁₀, and specifically includesmethyl, CF₃, CCl₃, CFCl₂, CF₂Cl, ethyl, CH₂CF₃, CF₂CF₃, propyl,isopropyl, cyclopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl,cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. The term includes both substituted and unsubstitutedalkyl groups, and particularly includes halogenated alkyl groups, andeven more particularly fluorinated alkyl groups. Non-limiting examplesof moieties with which the alkyl group can be substituted are selectedfrom the group consisting of halogen (fluoro, chloro, bromo or iodo),hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano,sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,either unprotected, or protected as necessary, as known to those skilledin the art, for example, as taught in Greene, et al., Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to a C₁ to C₄ saturated straight, branched, or if appropriate, acyclic (for example, cyclopropyl) alkyl group, including bothsubstituted and unsubstituted moieties.

The term “alkylamino” or “arylamino” refers to an amino group that hasone or two alkyl or aryl substituents, respectively. Unless otherwisespecifically stated in this application, when alkyl is a suitablemoiety, lower alkyl is preferred. Similarly, when alkyl or lower alkylis a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term “aryl”, as used herein, and unless otherwise specified, refersto phenyl, biphenyl, or naphthyl, and preferably phenyl. The termincludes both substituted and unsubstituted moieties. The aryl group canbe substituted with any described moiety, including, but not limited to,one or more moieties selected from the group consisting of halogen(fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition, 1991.

The term “alkaryl” or “alkylaryl” refers to an alkyl group with an arylsubstituent. The term aralkyl or arylalkyl refers to an aryl group withan alkyl substituent.

The term “halo”, as used herein, includes chloro, bromo, iodo, andfluoro.

The term “purine” or “pyrimidine” base includes, but is not limited to,adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-alkylaminopurine, N⁶-thioalkyl purine, N²-alkylpurines,N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimnidines,C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine,C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine,C⁵-iodopyrimidine, C⁶-iodo-pyrimidine, C⁵-Br-vinyl pyrimidine,C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Purine bases include, but are not limited to,guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.Functional oxygen and nitrogen groups on the base can be protected asnecessary or desired. Suitable protecting groups are well known to thoseskilled in the art, and include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups,and acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

The term “acyl” or “O-linked ester” refers to a group of the formulaC(O)R′, wherein R′ is an straight, branched, or cyclic alkyl (includinglower alkyl), amino acid, aryl including phenyl, alkaryl, aralkylincluding benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl suchas phenoxymethyl; or substituted alkyl (including lower alkyl), arylincluding phenyl optionally substituted with chloro, bromo, fluoro,iodo, C₁ to C₄ alkyl or C₁ to C₄ alkoxy, sulfonate esters such as alkylor aralkyl sulphonyl including methanesulfonyl, the mono, di ortriphosphate ester, trityl or monomethoxy-trityl, substituted benzyl,alkaryl, aralkyl including benzyl, alkoxyalkyl including methoxymethyl,aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimallycomprise a phenyl group. In particular, acyl groups include acetyl,trifluoroacetyl, methylacetyl, cyclopropylacetyl, cyclopropyl carboxy,propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl,phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl,α-methoxy-α-trifluoromethyl-phenylacetyl, bromoacetyl,2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl,2-chloro-2,2-diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl,chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl,bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl,chlorosulfonylacetyl, 3-methoxyphenylacetyl, phenoxyacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,7H-dodecafluoro-heptanoyl, perfluoro-heptanoyl,7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl,7-chloro-dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl,7H-dodeca-fluoroheptanoyl, nona-fluoro-3,6-dioxa-heptanoyl,nonafluoro-3,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl,methyl 3-amino-5-phenylthiophene-2-carboxyl,3,6-dichloro-2-methoxy-benzoyl, 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoyl,2-bromo-propionyl, omega-aminocaproyl, decanoyl, n-pentadecanoyl,stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O-acetylmandelyl,pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl,2,6-pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl,perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolylcarbonyl, perfluorocyclohexyl carboxyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,1-pyrrolidinecarbonyl, 4-phenylbenzoyl. When the term acyl is used, itis meant to be a specific and independent disclosure of acetyl,trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl, butyryl,hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl,diphenylacetyl, α-trifluoromethyl-phenylacetyl, bromoacetyl,4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl,2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl,perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearyl,3-cyclopentyl-propionyl, 1-benzene-carboxyl, pivaloyl acetyl,1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6-pyridinedicarboxyl,cyclopropane-carboxyl, cyclobutane-carboxyl, 4-methylbenzoyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,4-phenylbenzoyl.

The term “amino acid” includes naturally occurring and synthetic α, β γor δ amino acids, and includes but is not limited to, amino acids foundin proteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. Tables 1-24 set out examples of species within the presentinvention. When the term amino acid is used, it is considered to be aspecific and independent disclosure of each of the esters of α, β γ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations.

As used herein, the term “substantially free of” or “substantially inthe absence of” refers to a nucleoside composition that includes atleast 85 or 90% by weight, preferably 95%, 98%, 99% or 100% by weight,of the designated enantiomer of that nucleoside. In a preferredembodiment, in the methods and compounds of this invention, thecompounds are substantially free of enantiomers.

Similarly, the term “isolated” refers to a nucleoside composition thatincludes at least 85%, 90%, 95%, 98%, 99%, or 100% by weight, of thenucleoside, the remainder comprising other chemical species orenantiomers.

The term “host”, as used herein, refers to an unicellular ormulticellular organism in which the virus can replicate, including celllines and animals, and preferably a human. Alternatively, the host canbe carrying a part of the Flaviviridae viral genome, whose replicationor function can be altered by the compounds of the present invention.The term host specifically refers to infected cells, cells transfectedwith all or part of the Flaviviridae genome and animals, in particular,primates (including chimpanzees) and humans. In most animal applicationsof the present invention, the host is a human patient. Veterinaryapplications, in certain indications, however, are clearly anticipatedby the present invention (such as chimpanzees).

The term “pharmaceutically acceptable salt or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, phosphate ester, salt of an ester or a relatedgroup) of a nucleoside compound which, upon administration to a patient,provides the nucleoside compound. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids. Suitable salts include those derived fromalkali metals such as potassium and sodium, alkaline earth metals suchas calcium and magnesium, among numerous other acids well known in thepharmaceutical art. Pharmaceutically acceptable prodrugs refer to acompound that is metabolized, for example hydrolyzed or oxidized, in thehost to form the compound of the present invention. Typical examples ofprodrugs include compounds that have biologically labile protectinggroups on a functional moiety of the active compound. Prodrugs includecompounds that can be oxidized, reduced, aminated, deaminated,hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated,dealkylated, acylated, deacylated, phosphorylated, dephosphorylated toproduce the active compound. The compounds of this invention possessantiviral activity against a Flaviviridae, or are metabolized to acompound that exhibits such activity.

IV. Prodrugs and Derivatives

The active compound can be administered as any salt or prodrug that uponadministration to the recipient is capable of providing directly orindirectly the parent compound, or that exhibits activity itself.Nonlimiting examples are the pharmaceutically acceptable salts(alternatively referred to as “physiologically acceptable salts”), and acompound, which has been alkylated, acylated, or otherwise modified atthe 5′-position, or on the purine or pyrimidine base (a type of“pharmaceutically acceptable prodrug”). Further, the modifications canaffect the biological activity of the compound, in some cases increasingthe activity over the parent compound. This can easily be assessed bypreparing the salt or prodrug and testing its antiviral activityaccording to the methods described herein, or other methods known tothose skilled in the art.

A. Pharmaceutically Acceptable Salts

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Examples ofpharmaceutically acceptable salts are organic acid addition salts formedby addition of acids, which form a physiological acceptable anion, forexample, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorate, α-ketoglutarate,α-glycerophosphate, formate, fumarate, propionate, glycolate, lactate,pyruvate, oxalate, maleate, and salicylate. Suitable inorganic salts mayalso be formed, including, sulfate, nitrate, bicarbonate, carbonatesalts, hydrobromate and phosphoric acid. In a preferred embodiment, thesalt is a mono- or di-hydrochloride salt.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made. In one embodiment, the saltis a hydrochloride salt of the compound. In another embodiment, thepharmaceutically acceptable salt is a dihydrochloride salt.

B. Nucleotide Prodrug Formulations

The nucleosides described herein can be administered as a nucleotideprodrug to increase the activity, bioavailability, stability orotherwise alter the properties of the nucleoside. A number of nucleotideprodrug ligands are known. In general, alkylation, acylation or otherlipophilic modification of the mono-, di- or triphosphate of thenucleoside reduces polarity and allows passage into cells. Examples ofsubstituent groups that can replace one or more hydrogens on thephosphate moiety are alkyl, aryl, steroids, carbohydrates, includingsugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jonesand N. Bischoferger, Antiviral Research, 1995, 27:1-17. Any of these canbe used in combination with the disclosed nucleosides to achieve adesired effect.

In an alternative embodiment, the nucleoside is delivered as aphosphonate or a SATE derivative.

The active nucleoside can also be provided as a 2′, 3′ and/or5′-phosphoether lipid or a 2′, 3′ and/or 5′-ether lipid. Non-limitingexamples are described include the following references, which areincorporated by reference herein: Kucera, L. S., N. Iyer, E. Leake, A.Raben, Modest E. K., D. L. W., and C. Piantadosi. 1990. “Novelmembrane-interactive ether lipid analogs that inhibit infectious HIV-1production and induce defective virus formation.” AIDS Res. Hum. RetroViruses. 6:491-501; Piantadosi, C., J. Marasco C. J., S. L.Morris-Natschke, K. L. Meyer, F. Gumus, J. R. Surles, K. S. Ishaq, L. S.Kucera, N. Iyer, C. A. Wallen, S. Piantadosi, and E. J. Modest. 1991.“Synthesis and evaluation of novel ether lipid nucleoside conjugates foranti-HIV activity.” J. Med. Chem. 34:1408.1414; Hosteller, K. Y., D. D.Richman, D. A. Carson, L. M. Stuhmiller, G. M. T. van Wijk, and H. vanden Bosch. 1992. “Greatly enhanced inhibition of human immunodeficiencyvirus type I replication in CEM and HT4-6C cells by 3′-deoxythyminediphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymine.”Antimicrob. Agents Chemother. 36:2025.2029; Hosetler, K. Y., L. M.Stuhmiller, H. B. Lenting, H. van den Bosch, and D. D. Richman, 1990.“Synthesis and antiretroviral activity of phospholipid analogs ofazidothymine and other antiviral nucleosides.”J. Biol. Chem. 265:61127.

Nonlimiting examples of U.S. patents that disclose suitable lipophilicsubstituents that can be covalently incorporated into the nucleoside,preferably at the 2′, 3′ and/or 5′-OH position of the nucleoside orlipophilic preparations, include U.S. Pat. No. 5,149,794 (Sep. 22, 1992,Yatvin et al.); U.S. Pat. No. 5,194,654 (Mar. 16, 1993, Hostetler etal., U.S. Pat. No. 5,223,263 (Jun. 29, 1993, Hostetler et al.); U.S.Pat. No. 5,256,641 (Oct. 26, 1993, Yatvin et al.); U.S. Pat. No.5,411,947 (May 2, 1995, Hostetler et al.); U.S. Pat. No. 5,463,092 (Oct.31, 1995, Hostetler et al.); U.S. Pat. No. 5,543,389 (Aug. 6, 1996,Yatvin et al.); U.S. Pat. No. 5,543,390 (Aug. 6, 1996, Yatvin et at.);U.S. Pat. No. 5,543,391 (Aug. 6, 1996, Yatvin et al.); and U.S. Pat. No.5,554,728 (Sep. 10, 1996; Basava et al.), all of which are incorporatedherein by reference. Foreign patent applications that discloselipophilic substituents that can be attached to the nucleosides of thepresent invention, or lipophilic preparations, include WO 89/02733, WO90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721.

Aryl esters, especially phenyl esters, are also provided. Nonlimitingexamples are disclosed in DeLambert et al., J. Med. Chem. 37: 498(1994). Phenyl esters containing a carboxylic ester ortho to thephosphate are also provided. Khamnei and Torrence, J. Med. Chem.;39:4109-4115 (1996). In particular, benzyl esters, which generate theparent compound, in some cases using substituents at the ortho- orpara-position to accelerate hydrolysis, are provided. Examples of thisclass of prodrugs are described by Mitchell et al., J. Chem. Soc. PerkinTrans. I 2345 (1992); Brook, et al. WO 91/19721; and Glazier et al. WO91/19721.

Cyclic and noncyclic phosphonate esters are also provided. Nonlimitingexamples are disclosed in Hunston et al., J. Med. Chem. 27: 440-444(1984) and Starrett et al. J. Med. Chem. 37: 1857-1864 (1994).Additionally, cyclic 3′,5′-phosphate esters are provided. Nonlimitingexamples are disclosed in Meier et al. J. Med. Chem. 22: 811-815 (1979).Cyclic 1′,3′-propanyl phosphonate and phosphate esters, such as onescontaining a fused aryl ring, i.e. the cyclosaligenyl ester, are alsoprovided (Meier et al., Bioorg. Med. Chem. Lett. 7: 99-104 (1997)).Unsubstituted cyclic 1′,3′-propanyl esters of the monophosphates arealso provided (Farquhar et al., J. Med. Chem. 26: 1153 (1983); Farquharet al., J. Med. Chem. 28: 1358 (1985)) were prepared. In addition,cyclic 1′,3′-propanyl esters substituted with a pivaloyloxy methyloxygroup at C-1′ are provided (Freed et al., Biochem. Pharmac. 38: 3193(1989); Biller et al., U.S. Pat. No. 5,157,027).

Cyclic phosphoramidates are known to cleave in vivo by an oxidativemechanism. Therefore, in one embodiment of the present invention, avariety of substituted 1′,3′ propanyl cyclic phosphoramidates areprovided. Non-limiting examples are disclosed by Zon, Progress in Med.Chem. 19, 1205 (1982). Additionally, a number of 2′- and 3′-substitutedproesters are provided. 2′-Substituents include methyl, dimethyl, bromo,trifluoromethyl, chloro, hydroxy, and methoxy; 3′-substituents includingphenyl, methyl, trifluoromethyl, ethyl, propyl, i-propyl, andcyclohexyl. A variety of 1-substituted analogs are also provided.

Cyclic esters of phosphorus-containing compounds are also provided.Non-limiting examples are described in the following:

-   [1] di and tri esters of phosphoric acids as reported in Nifantyev    et al., Phosphorus, Sulfur Silicon and Related Eelements, 113: 1    (1996); Wijnberg et al., EP-180276 A1;-   [2] phosphorus (III) acid esters. Kryuchkov et al., Izv. Akad. Nauk    SSSR, Ser. Khim. 6: 1244 (1987). Some of the compounds were claimed    to be useful for the asymmetric synthesis of L-Dopa precursors.    Sylvain et al., DE3512781 A1;-   [3] phosphoramidates. Shih et al., Bull. Inst. Chem. Acad. Sin, 41:    9 (1994); Edmundson et al., J. Chem. Res. Synop. 5: 122 (1989); and-   [4] phosphonates. Neidlein et al., Heterocycles 35: 1185 (1993).

Further, nonlimiting examples of U.S. and International PatentApplications that disclose suitable cyclic phosphoramidate prodrugsinclude U.S. Pat. No. 6,312,662; WO 99/45016; WO 00/52015; WO 01/47935;and WO 01/18013 to Erion, et al. from Metabasis Therapeutics, Inc.Specifically, prodrugs of the formula below are provided:

wherein:

-   -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group containing 5-7 atoms, optionally 1        heteroatom, substituted with hydroxy, acyloxy,        alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon        atom that is three atoms from both O groups attached to the        phosphorus; or    -   together V and Z are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing 1 heteroatom, that is        fused to an aryl group at the beta and gamma position to the O        attached to the phosphorus;    -   together V and W are connected via an additional 3 carbon atoms        to form an optionally substituted cyclic group containing 6        carbon atoms and substituted with one substituent selected from        the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,        alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of        said carbon atoms that is three atoms from an O attached to the        phosphorus;    -   together Z and W are connected via an additional 3-5 atoms to        form a cyclic group, optionally containing one heteroatom, and V        must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   together W and W′ are connected via an additional 2-5 atoms to        form a cyclic group, optionally containing 0-2 heteroatoms, and        V must be aryl, substituted aryl, heteroaryl, or substituted        heteroaryl;    -   Z is selected from the group consisting of —CHR² OH, —CHR²        OC(O)R³, —CHR² OC(S)R³, —CHR² OC(S)OR³, —CHR² OC(O)SR³, —CHR²        OCO₂ R³, —OR², —SR², —CHR²N₃, —CH² aryl, —CH(aryl)OH, —CH(CH═CR²        ₂)OH, —CH(C.ident.CR²)OH, —R², —NR² ₂, —OCOR³, —OCO₂ R³, —SCOR³,        —SCO₂ R³, —NHCOR², —NHCO₂ R³, —CH₂ NHaryl, —(CH₂)_(p)—OR¹², and        —(CH₂)_(p)—SR¹²;    -   p is an integer 2 or 3;    -   with the provisos that:        -   a) V, Z, W, W′ are not all —H; and        -   b) when Z is —R², then at least one of V, W, and W′ is not            —H, alkyl, aralkyl, or alicyclic;    -   R² is selected from the group consisting of R³ and —H;    -   R³ is selected from the group consisting of alkyl, aryl,        alicyclic, and aralkyl;    -   R¹² is selected from the group consisting of —H, and lower acyl;    -   M is the biologically active agent, and that is attached to the        phosphorus in formula I via the 2′, 3′ and/or 5′-hydroxyl.

V. Combination or Alternation Therapy

The active compounds of the present invention can be administered incombination or alternation with another anti-flavivirus or pestivirusagent, or in particular an anti-HCV agent to treat any of the conditionsdescribed herein. In combination therapy, effective dosages of two ormore agents are administered together, whereas in alternation orsequential-step therapy, an effective dosage of each agent isadministered serially or sequentially. The dosages given will depend onabsorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. In preferred embodiments, an anti-HCV (or anti-pestivirusor anti-flavivirus) compound that exhibits an EC₅₀ of 10-15 μM, orpreferably less than 1-5 μM, is desirable.

It has been recognized that drug-resistant variants of flaviviruses,pestiviruses or HCV can emerge after prolonged treatment with anantiviral agent. Drug resistance most typically occurs by mutation of agene that encodes for an enzyme used in viral replication. The efficacyof a drug against the viral infection can be prolonged, augmented, orrestored by administering the compound in combination or alternationwith a second, and perhaps third, antiviral compound that induces adifferent mutation from that caused by the principle drug.Alternatively, the pharmacokinetics, biodistribution or other parameterof the drug can be altered by such combination or alternation therapy.In general, combination therapy is typically preferred over alternationtherapy because it induces multiple simultaneous stresses on the virus.

Any of the viral treatments described in the Background of the Inventioncan be used in combination or alternation with the compounds describedin this specification. Nonlimiting examples include:

-   -   1) Protease inhibitors

Examples include substrate-based NS3 protease inhibitors (Attwood etal., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood etal., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood etal., Preparation and use of amino acid derivatives as anti-viral agents,German Patent Pub. DE 19914474; Tung et al. Inhibitors of serineproteases, particularly hepatitis C virus NS3 protease, PCT WO98/17679), including alphaketoamides and hydrazinoureas, and inhibitorsthat terminate in an electrophile such as a boronic acid or phosphonate(Llinas-Brunet et al, Hepatitis C inhibitor peptide analogues, PCT WO99/07734); Non-substrate-based NS3 protease inhibitors such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,Biochemical and Biophysical Research Communications, 1997, 238, 643-647;Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186),including RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup; and Sch 68631, a phenanthrenequinone, an HCV protease inhibitor(Chu M. et al., Tetrahedron Letters 37:7229-7232, 1996).

Sch 351633, isolated from the fungus Penicillium griseofulvum, wasidentified as a protease inhibitor (Chu M. et al., Bioorganic andMedicinal Chemistry Letters 9:1949-1952). Eglin c, isolated from leech,is a potent inhibitor of several serine proteases such as S. griseusproteases A and B, α-chymotrypsin, chymase and subtilisin. Qasim M. A.et al., Biochemistry 36:1598-1607, 1997.

U.S. patents disclosing protease inhibitors for the treatment of HCVinclude, for example, U.S. Pat. No. 6,004,933 to Spruce et al. whichdiscloses a class of cysteine protease inhibitors for inhibiting HCVendopeptidase 2; U.S. Pat. No. 5,990,276 to Zhang et al. which disclosessynthetic inhibitors of hepatitis C virus NS3 protease; U.S. Pat. No.5,538,865 to Reyes et a; WO 02/008251 to Corvas International, Inc, andWO 02/08187 and WO 02/008256 to Schering Corporation. HCV inhibitortripeptides are disclosed in U.S. Pat. Nos. 6,534,523, 6,410,531, and6,420,380 to Boehringer Ingelheim and WO 02/060926 to Bristol MyersSquibb. Diaryl peptides as NS3 serine protease inhibitors of HCV aredisclosed in WO 02/48172 to Schering Corporation. Imidazoleidinones asNS3 serine protease inhibitors of HCV are disclosed in WO 02/08198 toSchering Corporation and WO 02/48157 to Bristol Myers Squibb. WO98/17679 to Vertex Pharmaceuticals and WO 02/48116 to Bristol MyersSquibb also disclose HCV protease inhibitors.

-   -   2) Thiazolidine derivatives which show relevant inhibition in a        reverse-phase HPLC assay with an NS3/4A fusion protein and        NS5A/5B substrate (Sudo K. et al., Antiviral Research, 1996, 32,        9-18), especially compound RD-1-6250, possessing a fused        cinnamoyl moiety substituted with a long alkyl chain, RD4 6205        and RD4 6193;    -   3) Thiazolidines and benzanilides identified in Kakiuchi N. et        al. J. EBS Letters 421, 217-220; Takeshita N. et al. Analytical        Biochemistry, 1997, 247, 242-246;    -   4) A phenan-threnequinone possessing activity against protease        in a SDS-PAGE and autoradiography assay isolated from the        fermentation culture broth of Streptomyces sp., Sch 68631        (Chu M. et al., Tetrahedron Letters, 1996, 37, 7229-7232), and        Sch 351633, isolated from the fungus Penicillium griseofulvum,        which demonstrates activity in a scintillation proximity assay        (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9,        1949-1952);    -   5) Helicase inhibitors (Diana G. D. et al., Compounds,        compositions and methods for treatment of hepatitis C, U.S. Pat.        No. 5,633,358; Diana G. D. et al., Piperidine derivatives,        pharmaceutical compositions thereof and their use in the        treatment of hepatitis C, PCT WO 97/36554);    -   6) Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et        al. Journal of Virology, 1999, 73, 1649-1654), and the natural        product cerulenin (Lohmann V. et al., Virology, 1998, 249,        108-118);    -   7) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)        complementary to sequence stretches in the 5′ non-coding region        (NCR) of the virus (Alt M. et al., Hepatology, 1995, 22,        707-717), or nucleotides 326-348 comprising the 3′ end of the        NCR and nucleotides 371-388 located in the core coding region of        the HCV RNA (Alt M. et al., Archives of Virology, 1997, 142,        589-599; Galderisi U. et al., Journal of Cellular Physiology,        1999, 181, 251-257);    -   8) Inhibitors of IRES-dependent translation (Ikeda N et al.,        Agent for the prevention and treatment of hepatitis C, Japanese        Patent Pub. JP-08268890; Kai Y. et al. Prevention and treatment        of viral diseases, Japanese Patent Pub. JP-10101591);    -   9) Ribozymes, such as nuclease-resistant ribozymes        (Maccjak, D. J. et al., Hepatology 1999, 30, abstract 995) and        those disclosed in U.S. Pat. No. 6,043,077 to Barber et al., and        U.S. Pat. Nos. 5,869,253 and 5,610,054 to Draper et al.; and    -   10) Nucleoside analogs have also been developed for the        treatment of Flaviviridae infections.    -   11) any of the compounds described by Idenix Pharmaceuticals in        International Publication Nos. WO 01/90121 and WO 01/92282.    -   12) Compound in other patent applications disclosing the use of        certain nucleoside analogs to treat hepatitis C virus include:        PCT/CA00/01316 (WO 01/32153; filed Nov. 3, 2000) and        PCT/CA01/00197 (WO 01/60315; filed Feb. 19, 2001) filed by        BioChem Pharma, Inc. (now Shire Biochem, Inc.); PCT/US02/01531        (WO 02/057425; filed Jan. 18, 2002) and PCT/US02/03086 (WO        02/057287; filed Jan. 18, 2002) filed by Merck & Co., Inc.,        PCT/EP01/09633 (WO 02/18404; published Aug. 21, 2001) filed by        Roche, and PCT Publication Nos. WO 01/79246 (filed Apr. 13,        2001), WO 02/32920 (filed Oct. 18, 2001) and WO 02/48165 by        Pharmasset, Ltd.    -   13) PCT Publication No. WO 99/43691 to Emory University,        entitled “2′-Fluoronucleosides” discloses the use of certain        2′-fluoronucleosides to treat HCV.    -   14) Other miscellaneous compounds including        1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134 to Gold et        al.), alkyl lipids (U.S. Pat. No. 5,922,757 to Chojkier et al.),        vitamin E and other antioxidants (U.S. Pat. No. 5,922,757 to        Chojkier et al.), squalene, amantadine, bile acids (U.S. Pat.        No. 5,846,964 to Ozeki et al.), N-(phosphonoacetyl)-L-aspartic        acid, (U.S. Pat. No. 5,830,905 to Diana et al.),        benzenedicarboxamides (U.S. Pat. No. 5,633,388 to Diana et al.),        polyadenylic acid derivatives (U.S. Pat. No. 5,496,546 to Wang        et al.), 2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687 to        Yarchoan et al.), benzimidazoles (U.S. Pat. No. 5,891,874 to        Colacino et al.), plant extracts (U.S. Pat. No. 5,837,257 to        Tsai et al., U.S. Pat. No. 5,725,859 to Omer et al., and U.S.        Pat. No. 6,056,961), and piperidenes (U.S. Pat. No. 5,830,905 to        Diana et al.).    -   15) Other compounds currently in preclinical or clinical        development for treatment of hepatitis c virus include:        Interleukin-10 by Schering-Plough, IP-501 by Interneuron,        Merimebodib (VX-497) by Vertex, AMANTADINE® (Symmetrel) by Endo        Labs Solvay, HEPTAZYME® by RPI, IDN-6556 by Idun Pharma.,        XTL-002 by XTL., HCV/MF59 by Chiron, CIVACIR® (Hepatitis C        Immune Globulin) by NABI, LEVOVIRIN® by ICN/Ribapharm,        VIRAMIDINE® by ICN/Ribapharm, ZADAXIN® (thymosin alpha-1) by Sci        Clone, thymosin plus pegylated interferon by Sci Clone, CEPLENE®        (histamine dihydrochloride) by Maxim, VX 950/LY 570310 by        Vertex/Eli Lilly, ISIS 14803 by Isis Pharmaceutical/Elan,        IDN-6556 by Idun Pharmaceuticals, Inc., JTK 003 by AKROS Pharma,        BILN-2061 by Boehringer Ingelheim, CellCept (mycophenolate        mofetil) by Roche, T67, a β-tubulin inhibitor, by Tularik, a        therapeutic vaccine directed to E2 by Innogenetics, FK788 by        Fujisawa Healthcare, Inc., IdB 1016 (Siliphos, oral        silybin-phosphatdylcholine phytosome), RNA replication        inhibitors (VP50406) by ViroPharma/Wyeth, therapeutic vaccine by        Intercell, therapeutic vaccine by Epimmune/Genencor, IRES        inhibitor by Anadys, ANA 245 and ANA 246 by Anadys,        immunotherapy (Therapore) by Avant, protease inhibitor by        Corvas/SChering, helicase inhibitor by Vertex, fusion inhibitor        by Trimeris, T cell therapy by CellExSys, polymerase inhibitor        by Biocryst, targeted RNA chemistry by PTC Therapeutics,        Dication by Immtech, Int., protease inhibitor by Agouron,        protease inhibitor by Chiron/Medivir, antisense therapy by AVI        BioPharma, antisense therapy by Hybridon, hemopurifier by        Aethlon Medical, therapeutic vaccine by Merix, protease        inhibitor by Bristol-Myers Squibb/Axys, Chron-VacC, a        therapeutic vaccine, by Tripep, UT 231B by United Therapeutics,        protease, helicase and polymerase inhibitors by Genelabs        Technologies, IRES inhibitors by Immusol, R803 by Rigel        Pharmaceuticals, INFERGEN® (interferon alphacon-1) by InterMune,        OMNIFERON® (natural interferon) by Viragen, ALBUFERON® by Human        Genome Sciences, REBIF® (interferon beta-1a) by Ares-Serono,        Omega Interferon by BioMedicine, Oral Interferon Alpha by        Amarillo Biosciences, interferon gamma, interferon tau, and        Interferon gamma-1b by InterMune.

VI. Pharmaceutical Compositions

Hosts, including humans, infected with pestivirus, flavivirus, HCVinfection, or any other condition described herein, or another organismreplicating through a RNA-dependent RNA viral polymerase, or fortreating any other disorder described herein, can be treated byadministering to the patient an effective amount of the active compoundor a pharmaceutically acceptable prodrug or salt thereof in the presenceof a pharmaceutically acceptable carrier or dilutent. The activematerials can be administered by any appropriate route, for example,orally, parenterally, intravenously, intradermally, subcutaneously, ortopically, in liquid or solid form.

A preferred dose of the compound for pestivirus, flavivirus or HCV willbe in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, ofbody weight per day, more generally 0.1 to about 100 mg per kilogrambody weight of the recipient per day. Lower doses may be preferable, forexample doses of 0.5-100 mg, 0.5-50 mg, 0.5-10 mg, or 0.5-5 mg perkilogram body weight per day. Even lower doses may be useful, and thusranges can include from 0.1-0.5 mg per kilogram body weight per day. Theeffective dosage range of the pharmaceutically acceptable salts andprodrugs can be calculated based on the weight of the parent nucleosideto be delivered. If the salt or prodrug exhibits activity in itself, theeffective dosage can be estimated as above using the weight of the saltor prodrug, or by other means known to those skilled in the art.

The compound is conveniently administered in unit any suitable dosageform, including but not limited to one containing 7 to 3000 mg,preferably 70 to 1400 mg of active ingredient per unit dosage form. Anoral dosage of 50-1000 mg is usually convenient, including in one ormultiple dosage forms of 50, 100, 200, 250, 300, 400, 500, 600, 700,800, 900 or 1000 mgs. Lower doses may be preferable, for example from10-100 or 1-50 mg. Also contemplated are doses of 0.1-50 mg, or 0.1-20mg or 0.1-10.0 mg. Furthermore, lower doses may be utilized in the caseof administration by a non-oral route, as, for example, by injection orinhalation.

Ideally the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.2 to 70 μM,preferably about 1.0 to 10 μM. This may be achieved, for example, by theintravenous injection of a 0.1 to 5% solution of the active ingredient,optionally in saline, or administered as a bolus of the activeingredient.

The concentration of active compound in the drug composition will dependon absorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcomposition. The active ingredient may be administered at once, or maybe divided into a number of smaller doses to be administered at varyingintervals of time.

A preferred mode of administration of the active compound is oral. Oralcompositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Pharmaceutically compatible bindingagents, and/or adjuvant materials can e included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

The compound can be administered as a component of an elixir,suspension, syrup, wafer, chewing gum or the like. A syrup may contain,in addition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salts thereofcan also be mixed with other active materials that do not impair thedesired action, or with materials that supplement the desired action,such as antibiotics, antifungals, anti-inflammatories, or otherantivirals, including other nucleoside compounds. Solutions orsuspensions used for parenteral, intradermal, sucutaneous, or topicalapplication can include the following components: a sterile diluent suchas water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parental preparation can be enclosed inampoules, disposable syringes or multiple dose vials made of glass orplastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation.

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) are also preferred aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811 (which is incorporated herein by reference inits entirety). For example, liposome formulations may be prepared bydissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is thenevaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound or itsmonophosphate, diphosphate, and/or triphosphate derivatives is thenintroduced into the container. The container is then swirled by hand tofree lipid material from the sides of the container and to disperselipid aggregates, thereby forming the liposomal suspension.

VII. Processes for the Preparation of Active Compounds

The nucleosides of the present invention can be synthesized by any meansknown in the art. In particular, the synthesis of the presentnucleosides can be achieved by either alkylating the appropriatelymodified sugar, followed by glycosylation or glycosylation followed byalkylation of the nucleoside. The following non-limiting embodimentsillustrate some general methodology to obtain the nucleosides of thepresent invention.

A. General Synthesis of 1′-C-Branched Nucleosides

1′-C-Branched ribonucleosides of the following structure:

wherein Base, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Y, W¹, W², W³, X,X¹, X² and X³ are as defined herein can be prepared by one of thefollowing general methods.1) Modification from the Lactone

The key starting material for this process is an appropriatelysubstituted lactone. The lactone can be purchased or can be prepared byany known means including standard epimerization, substitution andcyclization techniques. The lactone can be optionally protected with asuitable protecting group, preferably with an acyl or silyl group, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991. The protected lactone can then be coupled with a suitablecoupling agent, such as an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the appropriate non-protic solvent at a suitable temperature,to give the 1′-alkylated sugar.

The optionally activated sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with aLewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 1′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 1. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Alternative Method for the Preparation of 1′-C-Branched Nucleosides

The key starting material for this process is an appropriatelysubstituted hexose. The hexose can be purchased or can be prepared byany known means including standard epimerization (e.g. via alkalinetreatment), substitution and coupling techniques. The hexose can beselectively protected to give the appropriate hexa-furanose, as taughtby Townsend Chemistry of Nucleosides and Nucleotides, Plenum Press,1994.

The 1′-hydroxyl can be optionally activated to a suitable leaving groupsuch as an acyl group or a halogen via acylation or halogenation,respectively. The optionally activated sugar can then be coupled to theBASE by methods well known to those skilled in the art, as taught byTownsend Chemistry of Nucleosides and Nucleotides, Plenum Press, 1994.For example, an acylated sugar can be coupled to a silylated base with aLewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

The 1′-CH₂—OH, if protected, can be selectively deprotected by methodswell known in the art. The resultant primary hydroxyl can befunctionalized to yield various C-branched nucleosides. For example, theprimary hydroxyl can be reduced to give the methyl, using a suitablereducing agent. Alternatively, the hydroxyl can be activated prior toreduction to facilitate the reaction; i.e. via the Barton reduction. Inan alternate embodiment, the primary hydroxyl can be oxidized to thealdehyde, then coupled with a carbon nucleophile, such as a Grignardreagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ in TBAFwith the appropriate non-protic solvent at a suitable temperature.

In a particular embodiment, the 1′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 2. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In addition, the L-enantiomers corresponding to the compounds of theinvention can be prepared following the same general methods (1 or 2),beginning with the corresponding L-sugar or nucleoside L-enantiomer asstarting material.

B. General Synthesis of 2′-C-Branched Nucleosides

2′-C-Branched ribonucleosides of the following structure:

wherein Base, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, Y, W¹, W², W³, X, X¹,X² and X³ are as defined herein can be prepared by one of the followinggeneral methods.1. Glycosylation of the Nucleobase with an Appropriately Modified Sugar

The key starting material for this process is an appropriatelysubstituted sugar with a 2′-OH and 2′-H, with the appropriate leavinggroup (LG), for example an acyl group or a halogen. The sugar can bepurchased or can be prepared by any known means including standardepimerization, substitution, oxidation and reduction techniques. Thesubstituted sugar can then be oxidized with the appropriate oxidizingagent in a compatible solvent at a suitable temperature to yield the2′-modified sugar. Possible oxidizing agents are Jones reagent (amixture of chromic acid and sulfuric acid), Collins's reagent(dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate),pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂,ruthenium tetroxide, phase transfer catalysts such as chromic acid orpermanganate supported on a polymer, Cl₂-pyridine, H₂O₂-ammoniummolybdate, NaBrO₂-CAN, NaOCl in HOAc, copper chromite, copper oxide,Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent(aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the ketone with the appropriate non-protic solvent at asuitable temperature, yields the 2′-alkylated sugar. The alkylated sugarcan be optionally protected with a suitable protecting group, preferablywith an acyl or silyl group, by methods well known to those skilled inthe art, as taught by Greene et al. Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with aLewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 3. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Modification of a Pre-Formed Nucleoside

The key starting material for this process is an appropriatelysubstituted nucleoside with a 2′-OH and 2′-H. The nucleoside can bepurchased or can be prepared by any known means including standardcoupling techniques. The nucleoside can be optionally protected withsuitable protecting groups, preferably with acyl or silyl groups, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The appropriately protected nucleoside can then be oxidized with theappropriate oxidizing agent in a compatible solvent at a suitabletemperature to yield the 2′-modified sugar. Possible oxidizing agentsare Jones reagent (a mixture of chromic acid and sulfuric acid),Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridiniumchlorochromate), pyridinium dichromate, acid dichromate, potassiumpermanganate, MnO₂, ruthenium tetroxide, phase transfer catalysts suchas chromic acid or permanganate supported on a polymer, Cl₂-pyridine,H₂O₂-ammonium molybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite,copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verleyreagent (aluminum t-butoxide with another ketone) andN-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by GreeneGreene et al. ProtectiveGroups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 2′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 4. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.Therefore, the L-enantiomers can be corresponding to the compounds ofthe invention can be prepared following the same foregoing generalmethods, beginning with the corresponding L-sugar or nucleosideL-enantiomer as starting material.

C. General Synthesis of 3′-C-Branched Nucleosides

3′-C-Branched ribonucleosides of the following structure:

wherein Base, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Y, W¹, W², W³, X, X¹,X² and X³ are as defined herein can be prepared by one of the followinggeneral methods.1 Glycosylation of the Nucleobase with an Appropriately Modified Sugar

The key starting material for this process is an appropriatelysubstituted sugar with a 3′-OH and 3′-H, with the appropriate leavinggroup (LG), for example an acyl group or a halogen. The sugar can bepurchased or can be prepared by any known means including standardepimerization, substitution, oxidation and reduction techniques. Thesubstituted sugar can then be oxidized with the appropriate oxidizingagent in a compatible solvent at a suitable temperature to yield the3′-modified sugar. Possible oxidizing agents are Jones reagent (amixture of chromic acid and sulfuric acid), Collins's reagent(dipyridine Cr(VI) oxide, Corey's reagent (pyridinium chlorochromate),pyridinium dichromate, acid dichromate, potassium permanganate, MnO₂,ruthenium tetroxide, phase transfer catalysts such as chromic acid orpermanganate supported on a polymer, Cl₂-pyridine, H₂O₂-ammoniummolybdate, NaBrO₂—CAN, NaOCl in HOAc, copper chromite, copper oxide,Raney nickel, palladium acetate, Meerwin-Pondorf-Verley reagent(aluminum t-butoxide with another ketone) and N-bromosuccinimide.

Then coupling of an organometallic carbon nucleophile, such as aGrignard reagent, an organolithium, lithium dialkylcopper or R⁶—SiMe₃ inTBAF with the ketone with the appropriate non-protic solvent at asuitable temperature, yields the 3′-C-branched sugar. The 3′-C-branchedsugar can be optionally protected with a suitable protecting group,preferably with an acyl or silyl group, by methods well known to thoseskilled in the art, as taught by Greene et al. Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition, 1991.

The optionally protected sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with aLewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature. Alternatively, a halo-sugar can be coupled to a silylatedbase with the presence of trimethylsilyltriflate.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 5. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

2. Modification of a Pre-Formed Nucleoside

The key starting material for this process is an appropriatelysubstituted nucleoside with a 3′-OH and 3′-H. The nucleoside can bepurchased or can be prepared by any known means including standardcoupling techniques. The nucleoside can be optionally protected withsuitable protecting groups, preferably with acyl or silyl groups, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991.

The appropriately protected nucleoside can then be oxidized with theappropriate oxidizing agent in a compatible solvent at a suitabletemperature to yield the 2′-modified sugar. Possible oxidizing agentsare Jones reagent (a mixture of chromic acid and sulfuric acid),Collins's reagent (dipyridine Cr(VI) oxide, Corey's reagent (pyridiniumchlorochromate), pyridinium dichromate, acid dichromate, potassiumpermanganate, MnO₂, ruthenium tetroxide, phase transfer catalysts suchas chromic acid or permanganate supported on a polymer, Cl₂-pyridine,H₂O₂-ammonium molybdate, NaBrO₂-CAN, NaOCl in HOAc, copper chromite,copper oxide, Raney nickel, palladium acetate, Meerwin-Pondorf-Verleyreagent (aluminum t-butoxide with another ketone) andN-bromosuccinimide.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 3′-C-branched ribonucleoside is desired.The synthesis of a ribonucleoside is shown in Scheme 6. Alternatively,deoxyribo-nucleoside is desired. To obtain these nucleosides, the formedribonucleoside can optionally be protected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991, andthen the 2′-OH can be reduced with a suitable reducing agent.Optionally, the 2′-hydroxyl can be activated to facilitate reduction;i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.Therefore, the L-enantiomers can be corresponding to the compounds ofthe invention can be prepared following the same foregoing generalmethods, beginning with the corresponding L-sugar or nucleosideL-enantiomer as starting material.

D. General Synthesis of 4′-C-Branched Nucleosides

4′-C-Branched ribonucleosides of the following structure:

wherein Base, R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, Y, W¹, W², W³, X, X¹,X² and X³ are as defined herein can be prepared by one of the followinggeneral methods.1. Modification from the Pentodialdo-Furanose

The key starting material for this process is an appropriatelysubstituted pentodialdo-furanose. The pentodialdo-furanose can bepurchased or can be prepared by any known means including standardepimerization, substitution and cyclization techniques.

In a preferred embodiment, the pentodialdo-furanose is prepared from theappropriately substituted hexose. The hexose can be purchased or can beprepared by any known means including standard epimerization (e.g. viaalkaline treatment), substitution and coupling techniques. The hexosecan be either in the furanose form, or cyclized via any means known inthe art, such as methodology taught by Townsend Chemistry of Nucleosidesand Nucleotides, Plenum Press, 1994, preferably by selectivelyprotecting the hexose, to give the appropriate hexafuranose.

The 4′-hydroxymethylene of the hexafuranose then can be oxidized withthe appropriate oxidizing agent in a compatible solvent at a suitabletemperature to yield the 4′-aldo-modified sugar. Possible oxidizingagents are Swern reagents, Jones reagent (a mixture of chromic acid andsulfuric acid), Collins's reagent (dipyridine Cr(VI) oxide, Corey'sreagent (pyridinium chlorochromate), pyridinium dichromate, aciddichromate, potassium permanganate, MnO₂, ruthenium tetroxide, phasetransfer catalysts such as chromic acid or permanganate supported on apolymer, Cl₂-pyridine, H₂O₂-ammonium molybdate, NaBrO₂—CAN, NaOCl inHOAc, copper chromite, copper oxide. Raney nickel, palladium acetate,Meerwin-Pondorf-Verley reagent (aluminum t-butoxide with another ketone)and N-bromosuccinimide, though preferably using H₃PO₄, DMSO and DCC in amixture of benzene/pyridine at room temperature.

Then, the pentodialdo-furanose can be optionally protected with asuitable protecting group, preferably with an acyl or silyl group, bymethods well known to those skilled in the art, as taught by Greene etal. Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991. In the presence of a base, such as sodium hydroxide, theprotected pentodialdo-furanose can then be coupled with a suitableelectrophilic alkyl, halogeno-alkyl (i.e. CF₃), alkenyl or alkynyl (i.e.allyl), to obtain the 4′-alkylated sugar. Alternatively, the protectedpentodialdo-furanose can be coupled with the corresponding carbonyl,such as formaldehyde, in the presence of a base, such as sodiumhydroxide, with the appropriate polar solvent, such as dioxane, at asuitable temperature, which can then be reduced with an appropriatereducing agent to give the 4′-alkylated sugar. In one embodiment, thereduction is carried out using PhOC(S)Cl, DMAP, preferably inacetonitrile at room temperature, followed by treatment of ACCN and TMSSrefluxed in toluene.

The optionally activated sugar can then be coupled to the BASE bymethods well known to those skilled in the art, as taught by TownsendChemistry of Nucleosides and Nucleotides, Plenum Press, 1994. Forexample, an acylated sugar can be coupled to a silylated base with aLewis acid, such as tin tetrachloride, titanium tetrachloride ortrimethylsilyltriflate in the appropriate solvent at a suitabletemperature.

Subsequently, the nucleoside can be deprotected by methods well known tothose skilled in the art, as taught by Greene et al. Protective Groupsin Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

In a particular embodiment, the 4′-C-branched ribonucleoside is desired.Alternatively, deoxyribonucleoside is desired. To obtain thesedeoxyribo-nucleosides, a formed ribo-nucleoside can optionally beprotected by methods well known to those skilled in the art, as taughtby Greene et ac. Protective Groups in Organic Synthesis, John Wiley andSons, Second Edition, 1991, and then the 2′-OH can be reduced with asuitable reducing agent. Optionally, the 2′-hydroxyl can be activated tofacilitate reduction; i.e. via the Barton reduction.

In another embodiment of the invention, the L-enantiomers are desired.Therefore, the L-enantiomers can be corresponding to the compounds ofthe invention can be prepared following the same foregoing generalmethods, beginning with the corresponding L-pentodialdo-furanose asstarting material.

E. General Synthesis of 2′ and/or 3′-Prodrugs

The key starting material for this process is an appropriatelysubstituted 1′, 2′, 3′ or 4′-branched β-D or β-L nucleosides. Thebranched nucleoside can be purchased or can be prepared by any knownmeans including the techniques disclosed herein. The branched nucleosidecan be optionally protected with a suitable protecting group, preferablywith a silyl group, by methods well known to those skilled in the art,as taught by Greene et al. Protective Groups in Organic Synthesis, JohnWiley and Sons, Second Edition, 1991. The protected branched nucleosidecan then be coupled with a suitable acyl doner, such as an acyl chlorideand/or an acyl anhydride with the appropriate protic or aprotic solventat a suitable temperature, to give the 2′ and/or 3′ prodrug of 1′, 2′,3′ or 4′-branched β-D or β-L nucleoside. Alternatively, the protectedbranched nucleoside can then be coupled with a suitable acyl, such as acarboxylic acid, such as alkanoic acid and/or amino acid residue,optionally with a suitable coupling agent, with the appropriate aproticsolvent at a suitable temperature, to give the 2′ and/or 3′ prodrug of1′, 2′, 3′ or 4′-branched β-D or β-L nucleoside. Possible couplingreagents are any reagents that promote coupling, including but are notlimiting to, Mitsunobu reagents (e.g. diisopropyl azodicarboxylate anddiethyl azodicarboxylate) with triphenylphosphine or variouscarbodiimides.

For example, simple amino-alcohols can be esterified using acidchlorides in refluxing acetonitrile-benzene mixture (See Scheme 7 below:Synthetic Communications, 1978, 8(5), 327-333; hereby incorporated byreference). Alternatively, esterification can be achieved using ananhydride, as described in J. Am. Chem. Soc., 1999, 121(24), 5661-5664,which is hereby incorporated by reference. See FIGS. 2, 3 and 4.

The present invention is described by way of illustration, in thefollowing examples. It will be understood by one of ordinary skill inthe art that these examples are in no way limiting and that variationsof detail can be made without departing from the spirit and scope of thepresent invention.

Example 1: Preparation of 1′-C-Methylriboadenine Via6-amino-9-(1-Deoxy-β-D-psicofuranosyl)purine

Melting points were determined on a Mel-temp II apparatus and areuncorrected. NMR spectra were recorded on a Bruker 400 AMX spectrometerat 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR with TMS as internalstandard. Chemical shifts (δ) are reported in parts per million (ppm),and signals are reported as s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), or bs (broad singlet). IR spectra weremeasured on a Nicolet 510P FT-IR spectrometer. Mass spectra wererecorded on a Micromass Autospec high-resolution mass spectrometer. TLCwere performed on Uniplates (silica gel) purchased from Analtech Co.Column chromatography was performed using either silica gel-60 (220-440mesh) for flash chromatography or silica gel G (TLC grade, >440 mesh)for vacuum flash column chromatography. UV spectra were obtained on aBeckman DU 650 spectrophotometer. Elemental analysis was performed byAtlantic Microlab, Inc., Norcross, Ga., or Galbraith Laboratories, Inc.,Knoxville, Tenn. HPLC was performed with a Waters HPLC system (MilliporeCorporation, Milford, Mass.) equipped with a Model 600 controller, aModel 996 photodiode array detector and a Model 717 plus autosampler.Millennium 2010 software was used for system control, data acquisitionand processing. A chiralyser polarimetric detector, Perkin-Elmer Model241MC polarimeter (Wilton, Conn.), was used for the determination ofoptical rotations.

Synthesis of 1′-C-methylribo-8-methyladenine

The title compound could also be prepared according to a publishedprocedure (J. Farkas, and F. Sorm, “Nucleic acid components and theiranalogues. XCIV. Synthesis of6-amino-9-(1-deoxy-β-D-psicofuranosyl)purine” Collect. Czech. Chem.Commun. 1967, 32, 2663-2667; J. Farkas”, Collect. Czech. Chem. Commun.1966, 31, 1535) (Scheme 8).

In a similar manner, but using the appropriate sugar and purine bases,the following nucleosides of Formula XXIV are prepared.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 1.Alternatively, the following nucleosides of Formula XXV are prepared,using the appropriate sugar and pyrimidine bases.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 2.Alternatively, the following nucleosides of Formula XXVI are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R³, R⁶, X, and Base are defined in Table 3.

Alternatively, the following nucleosides of Formula XXVII are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 4.Alternatively, the following nucleosides of Formula XXVIII are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 5.Alternatively, the following nucleosides of Formula XXIX are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R⁶, R⁷, R⁸, X, R⁹, R¹⁰, and Base are defined in Table 6.

Example 2: Preparation of 2′-C-Methylribo-8-Methyladenine

The title compound was prepared according to a published procedure (R.E. Harry-O'kuru, J. M. Smith, and M. S. Wolfe, “A short, flexible routetoward 2′-C-branched ribonucleosides”, J. Org. Chem. 1997, 6, 1754-1759)(Scheme 9).

The 3′-prodrug of the 2′-branched nucleoside was prepared according topublished procedure (Synthetic Communications, 1978, 8(5), 327-333; J.Am. Chem. Soc., 1999, 121(24), 5661-5664). Alternatively, the2′-branched nucleoside can be esterified without protection (Scheme 9b).Carbonyldiimidazole (377 mg, 2.33 mmol) was added to a solution ofN-(tert-butoxycarbonyl)-L-valine (507 mg, 2.33 mmol) in 15 mL ofanhydrous tetrahydrofuran. The mixture was stirred at 20° C. for onehour and at 50° C. for 10 minutes and then added to a solution of4-Amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidine-2-one(500 mg, 1.95 mmol), 4-(dimethylamino)pyridine (25 mg, 0.195 mmol),triethylamine (5 mL) in anhydrous N,N-dimethylformamide (10 mL), whichis also stirring at 50° C. The reaction mixture was stirred at 50° C.for one hour and then examined by HPLC. HPLC analysis indicated theformation of 52% of the desired ester, 17% of starting material inaddition to undesired by-products. The 3′-OH of4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidine-2-onetends to react selectively when coupled with BOC-Val.

In a similar manner, but using the appropriate sugar and purine bases,the following nucleosides of Formula XXX are prepared.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 7.Alternatively, the following nucleosides of Formula XXXI are prepared,using the appropriate sugar and pyrimidine bases.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 8.Alternatively, the following nucleosides of Formula XXXII are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R³, R⁶, X, and Base are defined in Table 9.Alternatively, the following nucleosides of Formula XXXIII are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 10.Alternatively, the following nucleosides of Formula XXXIV are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 11.Alternatively, the following nucleosides of Formula XXXV are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R⁶, R⁷, R⁹, R¹⁰, X, and Base are defined in Table 12.

Example 3: Preparation of 3′-C-Methylribo-8-Methyladenine

The title compound can be prepared according to a published procedure(R. F. Nutt, M. J. Dickinson, F. W. Holly, and E. Walton,“Branched-chain sugar nucleosides. III. 3′-C-methyladenine”, J. Org.Chem. 1968, 33, 1789-1795) (Scheme 10).

In a similar manner, but using the appropriate sugar and purine bases,the following nucleosides of Formula XXXVI are prepared.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 13.Alternatively, the following nucleosides of Formula XXXVII are prepared,using the appropriate sugar and pyrimidine bases.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 14.Alternatively, the following nucleosides of Formula XXXVIII areprepared, using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R³, R⁶, X, and Base are defined in Table 15.Alternatively, the following nucleosides of Formula XXXIX are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 16.Alternatively, the following nucleosides of Formula XXXX are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 17.Alternatively, the following nucleosides of Formula XXXXI are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R⁶, R⁷, R⁵, R⁹, X, and Base are defined in Table 18.

Example 4: Preparation of1-O-Methyl-2,3-O-Isopropylidene-β-D-Ribofuranose—(1)

The title compound can be prepared according to a published procedure(Leonard, N. J.; Carraway, K. L. “5-Amino-5-deoxyribose derivatives.Synthesis and use in the preparation of “reversed” nucleosides” J.Heterocycl. Chem. 1966, 3, 485-489).

A solution of 50.0 g (0.34 mole) of dry D-ribose in 1.0 L of acetone,100 mL of 2,2-dimethoxypropane, 200 mL of methanol containing 20 mL ofmethanol saturated with hydrogen chloride at 0° C. was stirred overnightat room temperature. The resulting solution was neutralized withpyridine and evaporated under reduced pressure. The resulting oil waspartitioned between 400 mL of water and 400 mL of methylene chloride.The water layer was extracted twice with methylene chloride (400 mL).The combined organic extracts were dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography [eluent: stepwise gradient of methanol (1-2%)in methylene chloride] to give pure 1 (52.1 g, 75%) as a yellow syrup.¹H-NMR (CDCl₃): δ 5.00 (s, 1H, H-1), 4.86 (d, 1H, H-2, J₂₋₃=5.9 Hz),4.61 (d, 1H, H-3, J₃₋₂=5.9 Hz), 4.46 (t, 1H, H-4, J₄₋₅=2.7 Hz),3.77-3.61 (m, 2H, H-5 and H-5′), 3.46 (s, 1H, OCH₃), 3.0-2.4 (br s, 1H,OH-5), 1.51 (s, 3H CH₃), 1.34 (s, 3H CH₃); MS (matrix GT): FAB>0 m/z 173(M-OCH3)⁺.

Example 5: Preparation of1-O-Methyl-2,3-O-isopropylidene-β-D-pentodialdo-ribofuranose—(2)

The title compound can be prepared according to a published procedure(Jones, G. H.; Moffatt, J. G. Oxidation of carbohydrates by thesulfoxide-carbodiimide and related methods. Oxidation withdicyclohexylcarbodiimide-DMSO, diisopropylcarbodiimide-DMSO, aceticanhydride-DMSO, and phosphorus pentoxide-DMSO: in Methods inCarbohydrate Chemistry; Whisler, R. L. and Moffatt, J. L. Eds; AcademicPress: New York, 1972; 315-322).

Compound 1 was co-evaporated twice with anhydrous pyridine.Dicyclohexylcarbodi-imide (DCC, 137.8 g, 0.67 mol) was added to asolution of 1 (68.2 g. 0.33 mole) in anhydrous benzene (670 mL), DMSO(500 mL) and pyridine (13.4 mL). To the resulting solution, cooled to 0°C., was added a solution of anhydrous crystalline orthophosphoric acid(16.4 g, 0.167 mmol) in anhydrous DMSO (30 mL). The mixture was stirredfor 1.5 hours at 0° C. and 18 hours at room temperature under argonatmosphere, diluted with ethyl acetate (1000 mL). A solution of oxalicacid dihydrate (63.1 g, 038 mol) in DMSO (30 mL) was added and thereaction mixture was stirred at room temperature during 1 hour and thenfiltered to eliminate precipitated dicyclohexylurea (DCU). The filtratewas concentrated to a volume of about 600 mL under reduced pressure andneutralized with a saturated aqueous sodium hydrogen carbonate solution(400 mL). Brine (200 mL) was added and the organic layer was extractedwith ethyl acetate (4×1000 mL). The combined organic layers wereconcentrated to a volume of about 2000 mL, washed with a saturatedaqueous sodium hydrogen carbonate solution (2×700 mL), and with brine(2×700 mL) before being dried over sodium sulfate and evaporated underreduced pressure. A small fraction of the crude residue was purified onsilica gel chromatography [eluent: chloroform/ethyl ether, 8:2] in orderto confirm the structure of 2 which was obtained as a pale yellow solid.¹H-NMR (CDCl₃): δ 9.61 (s, 1H, H-5), 5.12 (s, 1H, H-1), 5.08 (d, 1H,H-2, J₂₋₃=5.9 Hz), 4.53 (d, 1H, H-3, J₃-2=6.0 Hz), 4.51 (s, 1H, H-4),3.48 (s, 1H, OCH₃), 1.56 (s, 3H CH₃), 1.36 (s, 3H CH₃); MS (matrix GT):FAB>0 m/z 203 (M+H)⁺, 171 (M-OCH₃)⁺.

Example 6: Preparation of4-C-Hydroxymethyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose—(3)

The title compound can be prepared according to a published procedure(Leland, D. L.; Kotick, M. P. “Studies on4-C-(hydroxymethyl)pentofuranose. Synthesis of9-[4-C-(hydroxymethyl)-a-L-threo-pentofuranosyl]adenine” Carbohydr. Res.1974, 38, C9-C11; Jones, G. H.; Taniguchi, M.; Tegg, D.; Moffatt, J. G.“4′-substituted nucleosides. 5. Hydroxylation of nucleoside5′-aldehydes” J. Org. Chem. 1979, 44, 1309-1317; Gunic, E.; Girardet,J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G. “Synthesis and cytotoxicityof 4′-C- and 5′-C-substituted Toyocamycins” Bioorg. Med. Chem. 2001, 9,163-170).

To a solution of the crude material (2) obtained above and 37% aqueousformaldehyde (167 mL) in dioxane (830 mL) was added aqueous sodiumhydroxyde (2N, 300 mL). The mixture was stirred at room temperature for4 hours and neutralized by addition of Dowex 50 W×2 (H⁺ form). The resinwas filtered, washed with methanol, and the combined filtrates wereconcentrated to dryness and coevaporated several times with absoluteethanol. Sodium formate which was precipitated from absolute ethanol wasremoved by filtration, the filtrate was concentrated to dryness and theresidue was purified by silica gel column chromatography [eluent:stepwise gradient of methanol (0-4%) in chloroform] to give pure 3 (42.2g, 54% from 1), which was recrystallized from cyclohexane. Mp=94-95(dec.) (lit. 94-96.5; 97-98: Refs: 3,4), ¹H-NMR (DMSO-d₆): δ 4.65 (s,1H, H-1), 4.44-4.37 (m, 3H, H-2, H-3 and OH-6), 4.27 (t, 1H, OH-5, J=5.6Hz, J=6.0 Hz), 3.42-3.34 (m, 2H, H-5 and H-6) 3.29 (dd, 1H, H-5′,J_(5′-OH)=5.4 Hz, J5-5′=11.4 Hz), 3.11 (dd, 1H, H-6′, J_(6′-OH)=5.7 Hz,J6-6′=10.9 Hz), 3.03 (s, 3H, OCH₃), 1.48 (s, 3H CH₃), 1.05 (s, 3H CH₃);MS (matrix GT): FAB>0 m/z 469 (2M+H)⁺, 235 (M+H)⁺, 203 (M-OCH₃)+ FAB<0m/z 233 (M−H)⁻.

Example 7: Preparation of6-O-Monomethoxytrityl-4-C-hydroxymethyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose—(4)

The title compound can be prepared according to a published procedure(Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G.“Synthesis and cytotoxicity of 4′-C- and 5′-C-substituted Toyocamycins”Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 3 (41.0 g, 175 mmol) in pyridine (700 ml) was added byportions dimethoxytrityl chloride (60.5 g, 178 mmol) at +4° C. Thereaction mixture was stirred for 3 hours at room temperature. Afteraddition of methanol, the reaction mixture was concentrated (200 ml) andthen dissolved with ethyl acetate (2 L). The organic layer was washedwith a 5% aqueous sodium hydrogen carbonate solution, with water anddried over sodium sulfate and then evaporated to dryness. Purificationby silica gel column chromatography [eluent: ethyl acetate/hexane 15/85]afforded pure 4 (63.0 g, 68%) as a syrup. ¹H-NMR (CDCl₃): δ 7.5-6.9 (m,13H, MMTr), 4.89 (s, 1H, H-1), 4.72-4.62 (m, 3H, H-2, H-3 and OH-5),3.82 (dd, 1H, H-5, J_(5-OH)=5.5 Hz, J5-5′=10.5 Hz), 3.79 (s, 6H, OCH3),3.54 (dd, 1H, H-5′, J_(5′-OH)=4.9 Hz, J_(5′-5)=10.5 Hz), 3.31 (s, 3H,OCH₃), 3.24 (d, 1H, H-6, J_(6-6′)=9.2 Hz), 3.13 (d, 1H, H-6′,J_(6′-6)=9.2 Hz), 1.24 (s, 3H CH₃), 1.15 (s, 3H CH₃); MS (matrix GT):FAB>0 m/z 303 (DMTr)⁺.

Example 8: Preparation of5-O-Benzoyl-4-C-hydroxymethyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribo-furanose—(5)

The title compound can be prepared according to a published procedure(Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G.“Synthesis and cytotoxicity of 4′-C- and 5′-C-substituted Toyocamycins”Bioorg. Med. Chem. 2001, 9, 163-170).

To a solution of 4 (2.51 g, 4.68 mmol) in anhydrous pyridine (37 mL) wasadded under argon benzoyl chloride (1.09 mL, 9.36 mmol) and the reactionmixture was stirred for 13 hours at to room temperature. Then thereaction was cooled to 0° C. and stopped with ice-cold water (100 mL).The water layer was extracted with methylene chloride (3 □ 200 mL). Thecombined organic layers were washed with a saturated aqueous sodiumhydrogen carbonate solution (2×150 mL), with water (lx 150 mL) and thendried over sodium sulfate and evaporated under reduced pressure. Theresidue was dissolved in 80% acetic acid (70.2 mL) and the mixture wasstirred at room temperature for 3 hr and concentrated to dryness.Purification by silica gel column chromatography [eluent: chloroform]afforded pure 5 (1.40 g, 88%) as a syrup. ¹H-NMR (CDCl₃): δ 8.1-7.4 (m,5H, C₆H₅CO), 5.08 (s, 1H, H-1), 4.77 (dd, 2H, H-2 and H-3, J=6.1 Hz,J=8.2 Hz), 4.51 (q, 2H, H-5 and H-5′, J=11.5 Hz, J_(5-5′)=23.8 Hz), 3.91(t, 2H, H-6 and H-6′, J=12.3 Hz), 4.38 (s, 1H, OCH₃), 2.2-1.8 (brs, 1H,OH-6), 1.57 (s, 3H CH₃), 1.38 (s, 3H CH₃); MS (matrix GT): FAB>0 m/z 677(2M+H)⁺, 339 (M+H)⁺, 307 (M-OCH₃)⁺, 105 (C₆H₅CO)⁺ FAB<0 m/z 121(C₆H₅CO₂)⁻.

Example 9: Preparation of5-O-Benzoyl-4-C-methyl-1-O-methyl-2,3-O-isopropylidene-β-D-ribofuranose—(6)

The title compound can be prepared according to a published procedure(Gunic, E.; Girardet, J.-L.; Pietrzkowski, Z.; Esler, C.; Wang, G.“Synthesis and cytotoxicity of 4′-C- and 5′-C-substituted Toyocamycins”Bioorg. Med. Chem. 2001, 9, 163-170).

A solution of 5 (37.6 g, 0.111 mol), 4-dimethylaminopyridine (DMAP, 40.7g, 0.333 mol) and phenoxythiocarbonyle chloride in anhydrousacetonitrile (1000 mL) was stirred at room temperature for 1 hour andconcentrated to dryness. The residue was dissolved in methylene chloride(500 mL) and successively washed with 0.2 M hydrochloric acid (2×500 mL)and water (500 mL) before being dried over sodium sulfate, evaporatedunder reduced pressure and coevaporated several times with anhydroustoluene. The crude material was dissolved in anhydrous toluene (880 mL)and tris(trimethylsilyl)silane (TMSS, 42.9 mL, 0.139 mol), and1,1′-azobis(cyclohexanecarbonitrile) (ACCN, 6.8 g, 27.8 mmol) wereadded. The reaction mixture was stirred under reflux for 45 minutes,cooled to room temperature and concentrated under reduced pressure. Theresulting residue was purified by silica gel column chromatography[eluent: stepwise gradient of diethyl ether (5-20%) in petroleum ether]to give pure 6 (26.4 g, 74%) as a pale yellow syrup. ¹H-NMR (DMSO-d₆): δ8.0-7.5 (m, 5H, C₆H₅CO), 4.85 (s, 1H, H-1), 4.63 (dd, 2H, H-2 and H-3,J=6.1 Hz, J=11.6 Hz), 4.24 (d, 1H, H-5, J_(5-5′)=11.1 Hz), 4.10 (d, 1H,H-5′, J_(5′-5)=11.1 Hz), 3.17 (s, 1H, OCH₃), 1.38 (s, 3H CH₃), 1.30 (s,3H CH₃), 1.25 (s, 3H CH₃); MS (matrix GT): FAB>0 m/z 291 (M-OCH₃)⁺, 105(C₆H₅CO)⁺ FAB<0 m/z 121 (C₆H₅CO₂)⁻.

Example 10: Preparation of5-O-Benzoyl-4-C-methyl-1,2,3-O-acetyl-α,β-D-ribofuranose—(7)

Compound 6 (22.5 g, 70 mmol) was suspended in a 80% aqueous acetic acidsolution (250 mL). The solution was heated at 100° C. for 3 hours. Thevolume was then reduced by half and coevaporated with absolute ethanoland pyridine. The oily residue was dissolved in pyridine (280 mL) andthen cooled at 0° C. Acetic anhydride (80 mL) and4-dimethylamino-pyridine (500 mg) were added. The reaction mixture wasstirred at room temperature for 3 hours and then concentrated underreduced pressure. The residue was dissolved with ethyl acetate (1 L) andsuccessively washed with a saturated aqueous sodium hydrogen carbonatesolution, a 1 M hydrochloric acid and water. The organic layer was driedover sodium sulfate and evaporated under reduced pressure. The resultingresidue was purified by silica gel column chromatography [eluent:stepwise gradient of diethyl ether (30-40%) in petroleum ether] to givepure 7 (16.2 g, 60%) as a pale yellow syrup. A small fraction of thematerial was re-purified on silica gel chromatography [same eluent:system] in order separate the α and the β anomers.

α anomer: ¹H-NMR (DMSO-d₆): δ 8.1-7.5 (m, 5H, C₆H₅CO), 6.34 (pt, 1H,H-1, J=2.4 Hz, J=2.1 Hz), 5.49 (m, 2H, H-2 and H-3), 4.33 (q, 2H, H-5and H-5′, J=11.6 Hz, J=18.7 Hz), 2.15 (s, 3H, CH₃CO₂), 2.11 (s, 3H,CH₃CO₂), 2.07 (s, 3H, CH₃CO₂), 1.37 (s, 3H, CH₃);

MS (matrix GT): FAB>0 m/z 335 (M-CH₃CO₂ ⁻)⁺, 275 (M-CH₃CO₂ ⁻+H)⁺, 105(C6H₅CO)⁺, 43 (CH₃CO)⁺ FAB<0 m/z 121 (C₆H₅CO₂)⁻, 59 (CH₃CO₂)⁻.

β anomer. ¹H-NMR (DMSO-d₆): δ 8.1-7.5 (m, 5H, C₆H₅CO), 5.99 (s, 1H,H-1), 5.46 (d, 1H, H-2, J₂₋₃=5.3 HZ), 5.30 (d, 1H, H-2, J₂₋₃=5.3 Hz),4.39 (d, 1H, H-5, J_(5-5′)=11.7 Hz), 4.19 (d, 1H, H-5′, J_(5′-5)=11.7Hz), 2.10 (s, 3H, CH₃CO₂), 2.06 (s, 3H, CH₃CO₂), 2.02 (s, 3H, CH₃CO₂),1.30 (s, 3H, CH₃); MS (matrix GT): FAB>0 m/z 335 (M-CH₃CO₂ ⁻)⁺, 275(M-CH₃CO₂ ⁻+H)⁺, 105 (C₆H₅CO)⁺, 43 (CH₃CO)⁺ FAB<0 m/z 121 (C₆H₅CO₂)⁻, 59(CH₃CO₂)⁻.

Example 11: Preparation ofO-6-Diphenylcarbamoyl-N²-isobutyryl-9-(2,3-di-O-acetyl-5-O-benzoyl-4-C-methyl-β-D-ribofuranosyl)-8-methylguanine—(18)

To a suspension of O-6-diphenylcarbamoyl-8-methyl-N²-isobutyrylguaninein anhydrous toluene (20 mL) was added N,O-bis(trimethylsilyl)acetamide(1.92 mL, 7.9 mmol). The reaction mixture was allowed to warm underreflux for 1 hour. Compound 7 (1.55 g, 3.93 mmol) was dissolved intoluene (10 mL) and trimethylsilyltrifluoro-methanesulfonate (TMSTf)(915 mL, 4.72 mmol) was added. The mixture was heated under reflux for30 minutes. The solution was then cooled to room temperature andneutralized with a 5% aqueous sodium hydrogen carbonate solution. Thereaction mixture was diluted with ethyl acetate (200 mL). The organicphase was washed with a 5% aqueous sodium hydrogen carbonate solution(150 mL) and with water (2×150 mL). The organic layer was dried overNa₂SO₄ and evaporated to dryness. The residue was purified by silica gelcolumn chromatography [eluent: stepwise gradient of diethyl ether(70-90%) in petroleum ether] to afford 18.

Example 12: Preparation of9-(4-C-methyl-β-D-ribofuranosyl)-8-methylguanine—(19)

The title compound can be prepared according to a published procedurefrom 18 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H.“Synthesis of 4′-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993,57, 1433-1438).

A solution of 18 in methanolic ammonia (previously saturated at −10° C.)(20 mL) was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween methylene chloride (60 mL) and water (60 mL). The aqueous layerwas washed with methylene chloride (2×60 mL), concentrated under reducedpressure. The residue was purified by an RP18 column chromatography[eluent water/acetonitrile 95/5] to afford 19.

Example 13:9-(2,3-di-O-acetyl-5-O-benzoyl-4-C-methyl-β-D-ribofuranosyl)-8-methyladenine—(20)

A solution of 7 (1.10 g, 2.79 mmol) in anhydrous acetonitrile (50 ml)was treated with 8-methyladenine and stannic chloride (SnCl₄, 660 μL,5.58 mmol) and stirred at room temperature overnight. The solution wasconcentrated under reduced pressure, diluted with chloroform (100 mL)and treated with a cold saturated aqueous solution of NaHCO₃ (100 ml).The mixture was filtered on celite, and the precipitate was washed withhot chloroform. The filtrates were combined, washed with water (100 ml)and brine (100 ml), dried (Na₂SO₄), and evaporated under reducedpressure. The residue was purified by silica gel column chromatography[eluent: stepwise gradient of methanol (3-5%) in dichloromethane] toafford 20.

Example 14: Preparation of9-(4-C-methyl-β-D-ribofuranosyl)-8-methyladenine—(21)

The title compound can be prepared according to a published procedurefrom 20 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H.“Synthesis of 4′-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993,57, 1433-1438).

A solution of 20 in methanolic ammonia (previously saturated at −10° C.)(50 mL) was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween methylene chloride (100 ml) and water (100 ml). The aqueouslayer was washed with methylene chloride (2×100 mL), and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography [eluent: stepwise gradient of methanol (10-30%) in ethylacetate] to afford 21.

In a similar manner, but using the appropriate sugar and purine bases,the following nucleosides of Formula XXXXII are prepared.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 19.

Example 15: Preparation of1-(5-O-Benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-6-methyluracil—(8)

A suspension of 6-methyluracil was treated with hexamethyldisilazane(HMDS, 21 mL) and a catalytic amount of ammonium sulfate during 17 hoursunder reflux. After cooling to room temperature, the mixture wasevaporated under reduced pressure, and the residue, obtained as acolorless oil, was diluted with anhydrous 1,2-dichloroethane (7.5 mL).To the resulting solution was added 7 (0.99 g, 2.51 mmol) in anhydrous1,2-dichloroethane (14 mL), followed by addition of trimethylsilyltrifluoromethanesulfonate (TMSTf, 0.97 mL, 5.02 mmol). The solution wasstirred for 2.5 hours at room temperature under argon atmosphere, thendiluted with chloroform (150 mL), washed with the same volume of asaturated aqueous sodium hydrogen carbonate solution and finally withwater (2×100 mL). The organic phase was dried over sodium sulfate, thenevaporated under reduced pressure. The resulting crude material waspurified by silica gel column chromatography [eluent: stepwise gradientof methanol (0-2%) in chloroform] to afford pure 8.

Example 16: Preparation of1-(4-C-methyl-β-D-ribofuranosyl)-6-methyluracil—(9)

The title compound can be prepared according to a published procedurefrom 8 (Waga, T.; Nishizaki, T.; Miyakawa, I.; Orhui, H.; Meguro, H.“Synthesis of 4′-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993,57, 1433-1438).

A solution of 8 in methanolic ammonia (previously saturated at −10° C.)(27 mL) was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween methylene chloride (40 mL) and water (40 mL). The aqueous layerwas washed with methylene chloride (2×40 mL), concentrated under reducedpressure and coevaporated several times with absolute ethanol.Recrystallization from a mixture absolute ethanol/methanol gave 9.

Example 17: Preparation of1-(5-O-Benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-4-thio-6-methyl-uracil—(10)

Lawesson's reagent (926 mg, 2.29 mmol) was added under argon to asolution of 8 in anhydrous 1,2-dichloroethane (65 mL) and the reactionmixture was stirred overnight under reflux. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography [eluent: stepwise gradient of methanol (1-2%) inchloroform] to give pure 10.

Example 18: Preparation of1-(4-C-methyl-β-D-ribofuranosyl)-4-thio-6-methyluracil—(11)

A solution of 10 in methanolic ammonia (previously saturated at −10° C.)(27 mL) was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween methylene chloride (40 ml) and water (40 mL). The aqueous layerwas washed with methylene chloride (2×40 mL), concentrated under reducedpressure. The crude material was purified by silica gel columnchromatography [eluent: stepwise gradient of methanol (5-7%) inmethylene chloride] to give 11, which was lyophilized.

Example 19: Preparation of1-(4-C-methyl-β-D-ribofuranosyl)-6-methylcytosine, hydrochloricform—(12)

Compound 11 was treated with methanolic ammonia (previously saturated at−10° C.), (12 mL) at 100° C. in a stainless-steel bomb for 3 hours, thencooled to room temperature. The solvent was evaporated under reducedpressure and the residue was partitioned between methylene chloride (40mL) and water (40 mL). The aqueous layer was washed with methylenechloride (2×40 mL), concentrated under reduced pressure. The crudematerial was purified by silica gel column chromatography [eluent:methylene chloride/methanol/ammonium hydroxide 65:30:5]. The collectedfractions were evaporated under reduced pressure and in absolute ethanol(6.3 mL). To the solution was added a 2N hydrochloric acid solution (1.5mL) and the mixture was stirred before being concentrated under reducedpressure. The procedure was repeated twice and 12 was precipitated fromabsolute ethanol.

Example 20: Preparation of1-(5-O-Benzoyl-4-C-methyl-2,3-O-acetyl-β-D-ribofuranosyl)-6-methylthymine—(13)

A suspension of 6-methylthymine was treated with hexamethyldisilazane(HMDS, 17 mL) and a catalytic amount of ammonium sulfate overnight underreflux. After cooling to room temperature, the mixture was evaporatedunder reduced pressure, and the residue, obtained as a colorless oil,was diluted with anhydrous 1,2-dichloroethane (6 mL). To the resultingsolution was added 7 (1.0 g, 2.53 mmol) in anhydrous 1,2-dichloroethane(14 mL), followed by addition of trimethylsilyltrifluoromethanesulfonate (TMSTf, 0.98 mL, 5.06 mmol). The solution wasstirred for 5 hours at room temperature under argon atmosphere, thendiluted with chloroform (150 mL), washed with the same volume of asaturated aqueous sodium hydrogen carbonate solution and finally withwater (2×100 mL). The organic phase was dried over sodium sulfate, thenevaporated under reduced pressure. The resulting crude material waspurified by silica gel column chromatography [eluent: 2% of methanol inchloroform] to afford pure 13.

Example 21: Preparation of1-(4-C-methyl-β-D-ribofuranosyl)-6-methylthymine—(14)

The title compound can be prepared according to a published procedurefrom 13 (Waga, T.; Nishizaki, T.; Miyakawa, L; Orhui, H.; Meguro, H.“Synthesis of 4′-C-methylnucleosides” Biosci. Biotechnol. Biochem. 1993,57, 1433-1438).

A solution of 13 in methanolic ammonia (previously saturated at −10° C.)(60 mL) was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was partitionedbetween methylene chloride (60 mL) and water (60 mL). The aqueous layerwas washed with methylene chloride (2×60 mL), concentrated under reducedpressure and coevaporated several times with absolute ethanol.Recrystallization from methanol gave 14.

Example 22: Preparation of1-(5,2,3-Tri-O-acetyl-4-C-methyl-β-D-ribofuranosyl)-6-methylthymine—(15)

A solution of 14 in anhydrous pyridine (7.4 mL) was treated with aceticanhydride (1.2 mL) and stirred at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography [eluent: stepwise gradientof methanol (0-5%) in methylene chloride] to afford 15.

Example 23: Preparation of1-(5,2,3-Tri-O-acetyl-4-C-methyl-β-D-ribofuranosyl)-4-thio-6-methylthymine—(16)

Lawesson's reagent (119 mg, 0.29 mmol) was added under argon to asolution of 15 in anhydrous 1,2-dichloroethane (11 mL) and the reactionmixture was stirred overnight under reflux. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography [eluent: stepwise gradient of methanol (1-2%) inchloroform] to give 16.

Example 24: Preparation of1-(4-C-methyl-β-D-ribofuranosyl)-5-methyl-6-methylcytosine—(17),hydrochloride form

Compound 16 was treated with methanolic ammonia (previously saturated at−10° C.), (10 mL) at 100° C. in a stainless-steel bomb for 3 hours, thencooled to room temperature. The solvent was evaporated under reducedpressure and the residue was partitioned between methylene chloride (30mL) and water (30 mL). The aqueous layer was washed with methylenechloride (2×30 mL), concentrated under reduced pressure. The crudematerial was purified by silica gel column chromatography [eluent: 20%methanol in methylene chloride] to afford 17. This compound wasdissolved in EtOH 100 (1.5 mL), treated with a 2N hydrochloric acidsolution (0.3 mL), and the mixture was stirred before being concentratedunder reduced pressure. The procedure was repeated twice and 17 wasprecipitated from absolute ethanol.

Alternatively, the following nucleosides of Formula XXXXIII areprepared, using the appropriate sugar and pyrimidine bases.

wherein R¹, R², R³, X¹, X², and Y are defined in Table 20.Alternatively, the following nucleosides of Formula XXXXIV are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R³, R⁶, X, and Base are defined in Table 21.Alternatively, the following nucleosides of Formula XXXXV are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 22.Alternatively, the following nucleosides of Formula XXXXVI are prepared,using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R², R⁶, X, and Base are defined in Table 23Alternatively, the following nucleosides of Formula XXXXVII areprepared, using the appropriate sugar and pyrimidine or purine bases.

wherein R¹, R⁶, R⁷, R⁸, R⁹, R¹⁰, X, and Base are defined in Table 24.

Tables 1-24 set out examples of species within the present invention.When the amino acid appears in the table, it is considered to be aspecific and independent disclosure of each of the esters of α, β γ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations. When the term acyl is usedin the tables, it is meant to be a specific and independent disclosureof any of the acyl groups as defined herein, including, but not limitedto, acetyl, trifluoroacetyl, methylacetyl, cyclopropylacetyl, propionyl,butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl,diphenylacetyl, α-trifluoromethyl-phenylacetyl, bromoacetyl,4-chloro-benzeneacetyl, 2-chloro-2,2-diphenylacetyl,2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl,perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, 2-thiopheneacetyl,tert-butylacetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl,methoxybenzoyl, 2-bromo-propionyl, decanoyl, n-pentadecanoyl, stearyl,3-cyclopentyl-carboxyl, 2,6-pyridinedicarboxyl, cyclopropane-carboxyl,cyclobutane-carboxyl, 4-methylbenzoyl, crotonyl,1-methyl-1H-indazole-3-carbonyl, 2-propenyl, isovaleryl,4-phenylbenzoyl.

VIII. Biological Assays

A number of assays are available to determine the potency of testcompounds against viruses. Several of these biological assays aredescribed in the examples below.

Example 25: Anti-Flavivirus or Pestivirus Activity

Compounds can exhibit anti-flavivirus or pestivirus activity byinhibiting flavivirus or pestivirus polymerase, by inhibiting otherenzymes needed in the replication cycle, or by other pathways.

Phosphorylation Assay of Nucleoside to Active Triphosphate

To determine the cellular metabolism of the compounds, HepG2 cells areobtained from the American Type Culture Collection (Rockville, Md.), andare grown in 225 cm² tissue culture flasks in minimal essential mediumsupplemented with non-essential amino acids, 1% penicillin-streptomycin.The medium is renewed every three days, and the cells are subculturedonce a week. After detachment of the adherent monolayer with a 10 minuteexposure to 30 mL of trypsin-EDTA and three consecutive washes withmedium, confluent HepG2 cells are seeded at a density of 2.5×10⁶ cellsper well in a 6-well plate and exposed to 10 μM of [³H] labeled activecompound (500 dpm/pmol) for the specified time periods. The cells aremaintained at 37° C. under a 5% CO₂ atmosphere. At the selected timepoints, the cells are washed three times with ice-coldphosphate-buffered saline (PBS). Intracellular active compound and itsrespective metabolites are extracted by incubating the cell pelletovernight at −20° C. with 60% methanol followed by extraction with anadditional 20 μL of cold methanol for one hour in an ice bath. Theextracts are then combined, dried under gentle filtered air flow andstored at −20° C. until HPLC analysis.

Bioavailability Assay in Cynomolgus Monkeys

Within 1 week prior to the study initiation, the cynomolgus monkey issurgically implanted with a chronic venous catheter and subcutaneousvenous access port (VAP) to facilitate blood collection and underwent aphysical examination including hematology and serum chemistryevaluations and the body weight was recorded. Each monkey (six total)receives approximately 250 μCi of ³H activity with each dose of activecompound at a dose level of 10 mg/kg at a dose concentration of 5 mg/mL,either via an intravenous bolus (3 monkeys, IV), or via oral gavage (3monkeys, PO). Each dosing syringe is weighed before dosing togravimetrically determine the quantity of formulation administered.Urine samples are collected via pan catch at the designated intervals(approximately 18-0 hours pre-dose, 0-4, 4-8 and 8-12 hours post-dosage)and processed. Blood samples are collected as well (pre-dose, 0.25, 0.5,1, 2, 3, 6, 8, 12 and 24 hours post-dosage) via the chronic venouscatheter and VAP or from a peripheral vessel if the chronic venouscatheter procedure should not be possible. The blood and urine samplesare analyzed for the maximum concentration (C_(max)), time when themaximum concentration is achieved (T_(max)), area under the curve (AUC),half life of the dosage concentration (T_(1/2)), clearance (CL), steadystate volume and distribution (V_(ss)) and bioavailability (F).

Bone Marrow Toxicity Assay

Human bone marrow cells are collected from normal healthy volunteers andthe mononuclear population are separated by Ficoll-Hypaque gradientcentrifugation as described previously by Sommadossi J-P, Carlisle R.“Toxicity of 3′-azido-3′-deoxythymidine and9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoieticprogenitor cells in vitro” Antimicrobial Agents and Chemotherapy 1987;31:452-454; and Sommadossi J-P, Schinazi R F, Chu C K, Xie M-Y.“Comparison of cytotoxicity of the (−)- and (+)-enantiomer of2′,3′-dideoxy-3′-thiacytidine in normal human bone marrow progenitorcells” Biochemical Pharmacology 1992; 44:1921-1925. The culture assaysfor CFU-GM and BFU-E are performed using a bilayer soft agar ormethylcellulose method. Drugs are diluted in tissue culture medium andfiltered. After 14 to 18 days at 37° C. in a humidified atmosphere of 5%CO₂ in air, colonies of greater than 50 cells are counted using aninverted microscope. The results are presented as the percent inhibitionof colony formation in the presence of drug compared to solvent controlcultures.

Mitochondria Toxicity Assay

HepG2 cells are cultured in 12-well plates as described above andexposed to various concentrations of drugs as taught by Pan-Zhou X-R,Cui L, Zhou X-J, Sommadossi J-P, Darley-Usmer V M. “Differential effectsof antiretroviral nucleoside analogs on mitochondrial function in HepG2cells” Antimicrob. Agents Chemother. 2000; 44:496-503. Lactic acidlevels in the culture medium after 4 day drug exposure are measuredusing a Boehringer lactic acid assay kit. Lactic acid levels arenormalized by cell number as measured by hemocytometer count.

Cytotoxicity Assay

Cells are seeded at a rate of between 5×10³ and 5×10⁴/well into 96-wellplates in growth medium overnight at 37° C. in a humidified CO₂ (5%)atmosphere. New growth medium containing serial dilutions of the drugsis then added. After incubation for 4 days, cultures are fixed in 50%TCA and stained with sulforhodamineB. The optical density was read at550 nm. The cytotoxic concentration was expressed as the concentrationrequired to reduce the cell number by 50% (CC₅₀).

Cell Protection Assay (CPA)

The assay is performed essentially as described by Baginski, S. G.;Pevear, D. C.; Seipel, M.; Sun, S. C. C.; Benetatos, C. A.; Chunduru, S.K.; Rice, C. M. and M. S. Collett “Mechanism of action of a pestivirusantiviral compound” PNAS USA 2000, 97(14), 7981-7986. MDBK cells (ATCC)are seeded onto 96-well culture plates (4,000 cells per well) 24 hoursbefore use. After infection with BVDV (strain NADL, ATCC) at amultiplicity of infection (MOI) of 0.02 plaque forming units (PFU) percell, serial dilutions of test compounds are added to both infected anduninfected cells in a final concentration of 0.5% DMSO in growth medium.Each dilution is tested in quadruplicate. Cell densities and virusinocula are adjusted to ensure continuous cell growth throughout theexperiment and to achieve more than 90% virus-induced cell destructionin the untreated controls after four days post-infection. After fourdays, plates are fixed with 50% TCA and stained with sulforhodamine B.The optical density of the wells is read in a microplate reader at 550nm. The 50% effective concentration (EC₅₀) values are defined as thecompound concentration that achieved 50% reduction of cytopathic effectof the virus.

Plaque Reduction Assay

For each compound the effective concentration is determined in duplicate24-well plates by plaque reduction assays. Cell monolayers are infectedwith 100 PFU/well of virus. Then, serial dilutions of test compounds inMEM supplemented with 2% inactivated serum and 0.75% of methyl celluloseare added to the monolayers. Cultures are further incubated at 37° C.for 3 days, then fixed with 50% ethanol and 0.8% Crystal Violet, washedand air-dried. Then plaques are counted to determine the concentrationto obtain 90% virus suppression.

Yield Reduction Assay

For each compound the concentration to obtain a 6-log reduction in viralload is determined in duplicate 24-well plates by yield reductionassays. The assay is performed as described by Baginski, S. G.; Pevear,D. C.; Seipel, M.; Sun, S. C. C.; Benetatos, C. A.; Chunduru, S. K.;Rice, C. M. and M. S. Collett “Mechanism of action of a pestivirusantiviral compound” PNAS USA 2000, 97(14), 7981-7986, with minormodifications. Briefly, MDBK cells are seeded onto 24-well plates (2×105cells per well) 24 hours before infection with BVDV (NADL strain) at amultiplicity of infection (MOI) of 0.1 PFU per cell. Serial dilutions oftest compounds are added to cells in a final concentration of 0.5% DMSOin growth medium. Each dilution is tested in triplicate. After threedays, cell cultures (cell monolayers and supernatants) are lysed bythree freeze-thaw cycles, and virus yield is quantified by plaque assay.Briefly, MDBK cells are seeded onto 6-well plates (5×105 cells per well)24 h before use. Cells are inoculated with 0.2 mL of test lysates for 1hour, washed and overlaid with 0.5% agarose in growth medium. After 3days, cell monolayers are fixed with 3.5% formaldehyde and stained with1% crystal violet (w/v in 50% ethanol) to visualize plaques. The plaquesare counted to determine the concentration to obtain a 6-log reductionin viral load.

Example 26: In Vitro Anti-Viral Activity

In vitro anti-viral activity was tested in the following cell lines:MT-4 for HIV; Vero 76, African green monkey kidney cells for SARS; BHKfor Bovine Viral Diarrhea Virus; Sb-1 for poliovirus Sabin type-1;CVB-2, CVB-3, CVB-4, and CVA-9 for Coxsackieviruses B-2, B-3, B-4 andA-9; and REO-1 for double-stranded RNA viruses. Note: BVDV=bovine viraldiarrhea virus; YFV=yellow fever virus; DENV=dengue virus; WNV=West Nilevirus; CVB-2=Coxsackie B-2 virus; Sb-1=Sabin type 1 poliomyelitis virus;and REO=double-stranded RNA Reovirus.

CC₅₀ and EC₅₀ Test Results forβ-D-2′-C-methyl-7-methyl-6-phenyl-3,3a,5,8a-tetrahydro-1,3,4,5,7a-penta-aza-s-indacen-8-one(Compound F)

CC₅₀ CC₅₀ CC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ EC₅₀ Compound MT-4 Vcro 76 BHKSb-1 CVB-2 CVB-3 CVB-4 CVA-9 REO-1 F >100 >100 >100 43 37 49 39 60 2

CC₅₀ Test Results forβ-D-2′-C-methyl-7-methyl-6-phenyl-3,3a,5,8a-tetrahydro-1,3,4,5,7a-penta-aza-s-indacen-8-one(Compound F)

Compound CC₅₀ BVDV YFV DENV 2 WNV CVB-2 Sb-1 REO F >100 10 2.5 1.3 1 3743 2

This invention has been described with reference to its preferredembodiments. Variations and modifications of the invention, will beobvious to those skilled in the art from the foregoing detaileddescription of the invention.

1. A compound of the Formula (XIII) or (XIV):

or a pharmaceutically acceptable salt thereof, wherein: R₃ is selectedfrom the group consisting of H; mono-, di-, and tri-phosphate or astabilized phosphate prodrug; acyl; a sulfonate ester; optionallysubstituted alkyl sulfonyl; optionally substituted arylsulfonyl; alipid; an amino acid; a carbohydrate; a peptide; cholesterol; and apharmaceutically acceptable leaving group which when administered invivo is capable of providing a compound wherein R₃ is independently H,or mono-, di- or triphosphate; B indicates a Spiro compound selectedfrom the group consisting of optionally substituted carbocycle oroptionally substituted heterocycle; Base is selected from the groupconsisting of:

wherein each R′, R″, R′″ and R″″ are independently selected from thegroup consisting of H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, cycloalkyl, Br-vinyl, —O-alkyl, O-alkenyl, O-alkynyl, O-aryl,O-aralkyl, —O-acyl, O-cycloalkyl, NH₂, NH-alkyl, N-dialkyl, NH-acyl,N-aryl, N-aralkyl, NH-cycloalkyl, SH, S-alkyl, S-acyl, S-aryl,S-cycloalkyl, S-aralkyl, F, Cl, Br, I, CN, COOH, CONH₂, CO₂-alkyl,CONH-alkyl, CON-dialkyl, OH, CF₃, CH₂OH, (CH₂)_(m)OH, (CH₂)_(m)NH₂,(CH₂)_(m)COOH, (CH₂)_(m)CN, (CH₂)_(m)NO₂ and (CH₂)_(m)CONH₂; m is 0 or1; W is C—R″ or N; T and V independently are CH or N; Q is CH, —CCl,—CBr, —CF, —CI, —CCN, —C—COOH, —C—CONH₂, or N; Q₁ and Q₂ independentlyare N or C—R; R is H, alkyl, or acyl; and Q₃, Q₄, Q₅ and Q₆independently are N or CH.
 2. A compound of claim 1, wherein B is a 3-7membered carbocyclic ring.
 3. A compound of claim 1, wherein B is a 3-7membered heterocyclic ring having one or more O, S and/or N atoms.
 4. Apharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable carrier.
 5. A method for the treatment of ahost infected with a hepatitis C virus, comprising administering aneffective treatment amount of a compound as claimed in claim 1, or apharmaceutically acceptable salt thereof.
 6. The method of claim 5,wherein the compound or pharmaceutically acceptable salt thereof isadministered in combination or alternation with a second anti-viralagent.
 7. The method of claim 6, wherein the second anti-viral agent isselected from the group consisting of an interferon, a ribavirin, aninterleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, aphenan-threnequinone, a thiazolidine derivative, a thiazolidine, abenzanilide, a phenan-threnequinone, a helicase inhibitor, a polymeraseinhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisensephosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependenttranslation, and a ribozyme.
 8. The method of claim 7, wherein thesecond anti-viral agent is an interferon.
 9. The method of claim 8,wherein the second anti-viral agent is selected from the groupconsisting of pegylated interferon alpha 2a, interferon alphacon-1,natural interferon, albuferon, interferon beta-1a, omega interferon,interferon alpha, interferon gamma, interferon tau, interferon delta andinterferon gamma-1b.
 10. The method of claim 5, wherein the compound orpharmaceutically acceptable salt thereof is in the form of a dosageunit.
 11. The method of claim 10, wherein the dosage unit contains 50 to1000 mg or 0.1 to 50 mg of the compound.
 12. The method of claim 10,wherein the dosage unit is a tablet or capsule.
 13. The method of claim5, wherein the host is a human.